Inhibitors of integrated stress response pathway

ABSTRACT

The present disclosure relates generally to therapeutic agents that may be useful as inhibitors of Integrated Stress Response (ISR) pathway.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the priority benefit of U.S. Provisional PatentApplication Nos. 62/598,377, filed Dec. 13, 2017, and 62/690,857, filedJun. 27, 2018, the disclosures of which are incorporated herein byreference in their entireties.

FIELD

The present disclosure relates generally to therapeutic agents that maybe useful as inhibitors of Integrated Stress Response (ISR) pathway.

BACKGROUND

Diverse cellular conditions and stresses activate a widely conservedsignaling pathway termed the Integrated Stress Response (ISR) pathway.The ISR pathway is activated in response to intrinsic and extrinsicstresses, such as viral infections, hypoxia, glucose and amino aciddeprivation, oncogene activation, UV radiation, and endoplasmicreticulum stress. Upon activation of ISR by one or more of thesefactors, the eukaryotic initiation factor 2 (eIF2, which is comprised ofthree subunits, α, β and γ) becomes phosphorylated in its α-subunit andrapidly reduces overall protein translation by binding to the eIF2Bcomplex. This phosphorylation inhibits the eIF2B-mediated exchange ofGDP for GTP (i.e., a guanine nucleotide exchange factor (GEF) activity),sequestering eIF2B in a complex with eIF2 and reducing general proteintranslation of most mRNA in the cell. Paradoxically, eIF2αphosphorylation also increases translation of a subset of mRNAs thatcontain one or more upstream open reading frames (uORFs) in their 5′untranslated region (UTR). These transcripts include the transcriptionalmodulator activating transcription factor 4 (ATF4), the transcriptionfactor CHOP, the growth arrest and DNA damage-inducible protein GADD34and the β-secretase BACE-1.

In animals, the ISR modulates a broad translational and transcriptionalprogram involved in diverse processes such as learning memory, immunity,intermediary metabolism, insulin production and resistance to unfoldedprotein stress in the endoplasmic reticulum, among others. Activation ofthe ISR pathway has also been associated with numerous pathologicalconditions including cancer, neurodegenerative diseases, metabolicdiseases (metabolic syndrome), autoimmune diseases, inflammatorydiseases, musculoskeletal diseases (such as myopathy), vasculardiseases, ocular diseases, and genetic disorders. Aberrant proteinsynthesis through eIF2α phosphorylation is also characteristic ofseveral other human genetic disorders, cystic fibrosis, amyotrophiclateral sclerosis, Huntington disease and prion disease.

BRIEF SUMMARY

Inhibitors of the Integrated Stress Response (ISR) pathway aredescribed, as are methods of making and using the compounds, or saltsthereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows percentage of ATF4 inhibition after induction withthapsigargin (Tg) in the presence of certain test compounds. Percentageof ATF4 inhibition was calculated as the percent reduction normalized toTg treatment (0% inhibition) and untreated cells (100% inhibition).

FIG. 2 shows protein synthesis levels in the presence of media alone orcertain test compounds in unstressed cells. The levels were normalizedto the media alone condition, which correspond to 100% proteinsynthesis.

FIG. 3A and FIG. 3B show percent recovery of protein synthesis in astressed cell in the presence of one of several test compounds at aconcentration of 100 nM (FIG. 3A) or 1 μM (FIG. 3B). The levels werenormalized to the media alone and to Tg alone conditions, whichcorrespond to 100% and 0% respectively. FIG. 3C shows percent ATF4inhibition for select compounds against percent recovery of proteinsynthesis.

FIG. 4A shows representative levels of ATF4 expression and β-actinexpression (control) in SH-SY5Y cells after being treated with cellculture media conditioned using wild-type CHO cells (wtCM) or 7PA2 CHOcells (7PA2CM).

FIG. 4B shows percent inhibition of ATF4 expression in SH-5Y5Y cellsafter incubation with conditioned media from 7PA2 CHO cells and one ofseveral test compounds. The levels were normalized to the media aloneand to conditioned media from 7PA2 CHO cells alone, which correspond to100% and 0% respectively.

FIG. 5A shows long-term potentiation (LTP) of a stimulated hippocampalslice from a WT C57BL/6 mouse or a transgenic APP/PS1 mouse with orwithout incubation with ISRIB. LTP was based on field excitatorypostsynaptic potential (fEPSP) slope, measured from 20 minutes prior totheta burst stimulation (TBS) to 60 minutes after TBS. FIG. 5B shows theresponses recorded in the last 10 minutes after conditioning stimulationof the slices from the WT C57BL/6 and APP/PS1 mice treated with ISRIB(APP+ISRIB), and from APP/PS1 mice treated with compound 3 (APP+Cmp3),or compound 152 (APP+Cmp152), or the vehicle (APP).

FIG. 6A shows results of an 8-arm radial water maze (RAWM) task used tomeasure learning in aged mice treated with compound 3 versus a vehiclecontrol (“Veh”). FIG. 6B shows levels of ATF4 expression normalized toβ-actin expression in hippocampi extracted from mice treated withcompound 3 versus a vehicle control (“Veh”). FIG. 6C shows individualdata points for the levels of ATF4 expression normalized to β-actinexpression in hippocampi extracted from mice treated with compound 3versus a vehicle control (“Veh”).

FIG. 7A shows learning memory test results of mice without a traumaticbrain injury (TBI), with TBI and untreated, and with TBI treated withcompound 3. FIG. 7B shows long-term memory test results of mice withouta traumatic brain injury (TBI), with TBI and untreated, and with TBItreated with compound 3. FIG. 7C shows social behavior (indicated bytime spent with a companion mouse) of mice without a traumatic braininjury (TBI), with TBI and untreated, and with TBI treated with compound3.

FIG. 8A shows protein synthesis in muscles from fasting mice or fastingmice treated with compound 3. Protein synthesis was normalized toβ-actin expression and percentage was calculated as the percent relativeto protein synthesis levels from control mice (Fed) which correspond to100%. FIG. 8B shows visualization of a muscle fiber cross-sectional area(CSA) stained with puromycin from a fed mouse, a fasting mouse, and afasting mouse treated with compound 3.

FIG. 9A and FIG. 9B show gastrocnemius weight from mice that were fed,fasted, or fasted with compound 3 (FIG. 9A) or compound 152 (FIG. 9B)administration. FIG. 9C and FIG. 9D show percent of protein synthesisfrom mice that were fed, fasted, or fasted with compound 3 (FIG. 9C) orcompound 152 (FIG. 9D) administration, normalized to I3-actin expressionand percentage calculated as the percent relative to protein synthesislevels from fed mice. FIG. 9E and FIG. 9F shows Atrogin-1 expression ingastrocnemius from mice that were fed, fasted, or fasted and treatedwith compound 3 (FIG. 9E) or compound 152 (FIG. 9F), normalized toβ-actin expression and fold change calculated as the levels relative tothe expression levels from fed mice. FIG. 9G shows visualization of amuscle fiber cross-sectional area (CSA) stained for ATF4 from a fedmouse, a fasting mouse, and a fasting mouse treated with compound 152.

FIG. 10A-C shows protein synthesis in the gastrocnemius (FIG. 10A),tibialis anterior (FIG. 10B) and quadriceps (FIG. 10C) muscles for themobile hindlimb and the immobilized hindlimb (triggeringimmobilization-induced muscle atrophy) in mice with unilateral hindlimbimmobilization, treated either with a vehicle control or compound 3. Thelevels were normalized to β-actin expression and percentage wascalculated as the percent relative to protein synthesis levels frommobile limb of control mice (vehicle-treated) which correspond to 100%.FIG. 10D shows visualization of a muscle fiber cross-sectional area(CSA) of gastrocnemius from mobile or immobile hind limbs stained forATF4.

FIG. 11A-C shows muscle weight of gastrocnemius (FIG. 11A), quadriceps(FIG. 11B), and tibialis anterior (FIG. 11C) muscles of control, micewith cachexia induced muscle atrophy, and mice with cachexia inducedmuscle atrophy treated with compound 3. FIG. 11D-F shows percent proteinsynthesis (normalized to β-actin expression) in gastrocnemius (FIG.11D), quadriceps (FIG. 11E), and tibialis anterior (FIG. 11F) muscles ofcontrol, mice with cachexia induced muscle atrophy, and mice withcachexia induced muscle atrophy treated with compound 3. Cachexia wasinduced by injecting mice with CT26 colon carcinoma cells in the flankof each animal.

FIG. 12A-12C shows tumor volume (FIG. 12A), tumor weight (FIG. 12B), andtumor density (FIG. 12C) of a subcutaneously injected CT26 coloncarcinoma cell line tumor from untreated (vehicle) mice or mice treatedwith compound 3 for 13 days, starting 6 days post tumor injection.

FIG. 13A shows relative fluorescence intensity (RFU) of GFP resultingfrom cell-free expression in a system treated with compound 152,compound 153, or a vehicle control. FIG. 13B compares the RFU from GFPcell-free expression systems treated with compound 152, compound 153, orvehicle control after 6 hours.

FIG. 14A and FIG. 14B show an SDS-PAGE gel of yeast cells engineered toexpress phospholipase C (PLC) under a methanol-inducible promoter(pAOX-PLC; FIG. 14A) or a constitutive promoter (pGAP-PLC; FIG. 14B),cultured in the presence of compound 152 or a control. The arrow in eachfigure indicates PLC.

FIG. 14C and FIG. 14D shows activity of PLC secreted from yeast cellsengineered to express phospholipase C (PLC) under a methanol-induciblepromoter (pAOX-PLC; FIG. 14C) or a constitutive promoter (pGAP-PLC; FIG.14D), cultured in the presence of compound 152 or a control, andindicated by fold-change relative to the control.

FIG. 15A shows an SDS-PAGE gel of secreted proteins from CHO cellscultured in the presence of 1 μm, 5 μm, or 10 μm of compound 152 orcompound 153 for 24 hours. The secreted proteins were quantitatedrelative to a control, as shown in FIG. 15B.

DETAILED DESCRIPTION Definitions

For use herein, unless clearly indicated otherwise, use of the terms“a”, “an” and the like refers to one or more.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. For example, description referring to “about X” includes descriptionof “X”.

“Alkyl” as used herein refers to and includes, unless otherwise stated,a saturated linear (i.e., unbranched) or branched univalent hydrocarbonchain or combination thereof, having the number of carbon atomsdesignated (i.e., C₁-C₁₀ means one to ten carbon atoms). Particularalkyl groups are those having 1 to 20 carbon atoms (a “C₁-C₂₀ alkyl”),having 1 to 10 carbon atoms (a “C₁-C₁₀ alkyl”), having 6 to 10 carbonatoms (a “C₆-C₁₀ alkyl”), having 1 to 6 carbon atoms (a “C₁-C₆ alkyl”),having 2 to 6 carbon atoms (a “C₂-C₆ alkyl”), or having 1 to 4 carbonatoms (a “C₁-C₄ alkyl”). Examples of alkyl groups include, but are notlimited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl,t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,n-nonyl, n-decyl, and the like.

“Alkylene” as used herein refers to the same residues as alkyl, buthaving bivalency. Particular alkylene groups are those having 1 to 20carbon atoms (a “C₁-C₂₀ alkylene”), having 1 to 10 carbon atoms (a“C₁-C₁₀ alkylene”), having 6 to 10 carbon atoms (a “C₆-C₁₀ alkylene”),having 1 to 6 carbon atoms (a “C₁-C₆ alkylene”), 1 to 5 carbon atoms (a“C₁-C₅ alkylene”), 1 to 4 carbon atoms (a “C₁-C₄ alkylene”) or 1 to 3carbon atoms (a “C₁-C₃ alkylene”). Examples of alkylene include, but arenot limited to, groups such as methylene (—CH₂—), ethylene (—CH₂CH₂—),propylene (—CH₂CH₂CH₂—), isopropylene (—CH₂CH(CH₃)—), butylene(—CH₂(CH₂)₂CH₂—), isobutylene (—CH₂CH(CH₃)CH₂—), pentylene(—CH₂(CH₂)₃CH₂—), hexylene (—CH₂(CH₂)₄CH₂—), heptylene (—CH₂(CH₂)₅CH₂—),octylene (—CH₂(CH₂)₆CH₂—), and the like.

“Alkenyl” as used herein refers to and includes, unless otherwisestated, an unsaturated linear (i.e., unbranched) or branched univalenthydrocarbon chain or combination thereof, having at least one site ofolefinic unsaturation (i.e., having at least one moiety of the formulaC═C) and having the number of carbon atoms designated (i.e., C₂-C₁₀means two to ten carbon atoms). An alkenyl group may have “cis” or“trans” configurations, or alternatively have “E” or “Z” configurations.Particular alkenyl groups are those having 2 to 20 carbon atoms (a“C₂-C₂₀ alkenyl”), having 6 to 10 carbon atoms (a “C₆-C₁₀ alkenyl”),having 2 to 8 carbon atoms (a “C₂-C₈ alkenyl”), having 2 to 6 carbonatoms (a “C₂-C₆ alkenyl”), or having 2 to 4 carbon atoms (a “C₂-C₄alkenyl”). Examples of alkenyl group include, but are not limited to,groups such as ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl),2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl,buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, pent-1-enyl, pent-2-enyl,hex-1-enyl, hex-2-enyl, hex-3-enyl, and the like.

“Alkenylene” as used herein refers to the same residues as alkenyl, buthaving bivalency. Particular alkenylene groups are those having 2 to 20carbon atoms (a “C₂-C₂₀ alkenylene”), having 2 to 10 carbon atoms (a“C₂-C₁₀ alkenylene”), having 6 to 10 carbon atoms (a “C₆-C₁₀alkenylene”), having 2 to 6 carbon atoms (a “C₂-C₆ alkenylene”), 2 to 4carbon atoms (a “C₂-C₄ alkenylene”) or 2 to 3 carbon atoms (a “C₂-C₃alkenylene”). Examples of alkenylene include, but are not limited to,groups such as ethenylene (or vinylene) (—CH═CH—), propenylene(—CH═CHCH₂—), 1,4-but-1-enylene (—CH═CH—CH₂CH₂—), 1,4-but-2-enylene(—CH₂CH═CHCH₂—), 1,6-hex-1-enylene (—CH═CH—(CH₂)₃CH₂—), and the like.

“Alkynyl” as used herein refers to and includes, unless otherwisestated, an unsaturated linear (i.e., unbranched) or branched univalenthydrocarbon chain or combination thereof, having at least one site ofacetylenic unsaturation (i.e., having at least one moiety of the formulaC≡C) and having the number of carbon atoms designated (i.e., C₂-C₁₀means two to ten carbon atoms). Particular alkynyl groups are thosehaving 2 to 20 carbon atoms (a “C₂-C₂₀ alkynyl”), having 6 to 10 carbonatoms (a “C₆-C₁₀ alkynyl”), having 2 to 8 carbon atoms (a “C₂-C₈alkynyl”), having 2 to 6 carbon atoms (a “C₂-C₆ alkynyl”), or having 2to 4 carbon atoms (a “C₂-C₄ alkynyl”). Examples of alkynyl groupinclude, but are not limited to, groups such as ethynyl (or acetylenyl),prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl,but-3-ynyl, and the like.

“Alkynylene” as used herein refers to the same residues as alkynyl, buthaving bivalency. Particular alkynylene groups are those having 2 to 20carbon atoms (a “C₂-C₂₀ alkynylene”), having 2 to 10 carbon atoms (a“C₂-C₁₀ alkynylene”), having 6 to 10 carbon atoms (a “C₆-C₁₀alkynylene”), having 2 to 6 carbon atoms (a “C₂-C₆ alkynylene”), 2 to 4carbon atoms (a “C₂-C₄ alkynylene”) or 2 to 3 carbon atoms (a “C₂-C₃alkynylene”). Examples of alkynylene include, but are not limited to,groups such as ethynylene (or acetylenylene) (—C≡C—), propynylene(—C≡CCH₂—), and the like.

“Cycloalkyl” as used herein refers to and includes, unless otherwisestated, saturated cyclic univalent hydrocarbon structures, having thenumber of carbon atoms designated (i.e., C₃-C₁₀ means three to tencarbon atoms). Cycloalkyl can consist of one ring, such as cyclohexyl,or multiple rings, such as adamantyl. A cycloalkyl comprising more thanone ring may be fused, spiro or bridged, or combinations thereof.Particular cycloalkyl groups are those having from 3 to 12 annularcarbon atoms. A preferred cycloalkyl is a cyclic hydrocarbon having from3 to 8 annular carbon atoms (a “C₃-C₈ cycloalkyl”), having 3 to 6 carbonatoms (a “C₃-C₆ cycloalkyl”), or having from 3 to 4 annular carbon atoms(a “C₃-C₄ cycloalkyl”). Examples of cycloalkyl include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, norbornyl, and the like.

“Cycloalkylene” as used herein refers to the same residues ascycloalkyl, but having bivalency. Cycloalkylene can consist of one ringor multiple rings which may be fused, spiro or bridged, or combinationsthereof. Particular cycloalkylene groups are those having from 3 to 12annular carbon atoms. A preferred cycloalkylene is a cyclic hydrocarbonhaving from 3 to 8 annular carbon atoms (a “C₃-C₈ cycloalkylene”),having 3 to 6 carbon atoms (a “C₃-C₆ cycloalkylene”), or having from 3to 4 annular carbon atoms (a “C₃-C₄ cycloalkylene”). Examples ofcycloalkylene include, but are not limited to, cyclopropylene,cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene,norbornylene, and the like. A cycloalkylene may attach to the remainingstructures via the same ring carbon atom or different ring carbon atoms.When a cycloalkylene attaches to the remaining structures via twodifferent ring carbon atoms, the connecting bonds may be cis- or trans-to each other. For example, cyclopropylene may include1,1-cyclopropylene and 1,2-cyclopropylene (e.g., cis-1,2-cyclopropyleneor trans-1,2-cyclopropylene), or a mixture thereof.

“Cycloalkenyl” refers to and includes, unless otherwise stated, anunsaturated cyclic non-aromatic univalent hydrocarbon structure, havingat least one site of olefinic unsaturation (i.e., having at least onemoiety of the formula C═C) and having the number of carbon atomsdesignated (i.e., C₂-C₁₀ means two to ten carbon atoms). Cycloalkenylcan consist of one ring, such as cyclohexenyl, or multiple rings, suchas norbornenyl. A preferred cycloalkenyl is an unsaturated cyclichydrocarbon having from 3 to 8 annular carbon atoms (a “C₃-C₈cycloalkenyl”). Examples of cycloalkenyl groups include, but are notlimited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,norbornenyl, and the like.

“Cycloalkenylene” as used herein refers to the same residues ascycloalkenyl, but having bivalency.

“Aryl” or “Ar” as used herein refers to an unsaturated aromaticcarbocyclic group having a single ring (e.g., phenyl) or multiplecondensed rings (e.g., naphthyl or anthryl) which condensed rings may ormay not be aromatic. Particular aryl groups are those having from 6 to14 annular carbon atoms (a “C₆-C₁₄ aryl”). An aryl group having morethan one ring where at least one ring is non-aromatic may be connectedto the parent structure at either an aromatic ring position or at anon-aromatic ring position. In one variation, an aryl group having morethan one ring where at least one ring is non-aromatic is connected tothe parent structure at an aromatic ring position.

“Arylene” as used herein refers to the same residues as aryl, but havingbivalency. Particular arylene groups are those having from 6 to 14annular carbon atoms (a “C₆-C₁₄ arylene”).

“Heteroaryl” as used herein refers to an unsaturated aromatic cyclicgroup having from 1 to 14 annular carbon atoms and at least one annularheteroatom, including but not limited to heteroatoms such as nitrogen,oxygen, and sulfur. A heteroaryl group may have a single ring (e.g.,pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl,benzothienyl) which condensed rings may or may not be aromatic.Particular heteroaryl groups are 5 to 14-membered rings having 1 to 12annular carbon atoms and 1 to 6 annular heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, 5 to 10-membered ringshaving 1 to 8 annular carbon atoms and 1 to 4 annular heteroatomsindependently selected from nitrogen, oxygen, and sulfur, or 5, 6 or7-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annularheteroatoms independently selected from nitrogen, oxygen, and sulfur. Inone variation, particular heteroaryl groups are monocyclic aromatic 5-,6- or 7-membered rings having from 1 to 6 annular carbon atoms and 1 to4 annular heteroatoms independently selected from nitrogen, oxygen andsulfur. In another variation, particular heteroaryl groups arepolycyclic aromatic rings having from 1 to 12 annular carbon atoms and 1to 6 annular heteroatoms independently selected from nitrogen, oxygen,and sulfur. A heteroaryl group having more than one ring where at leastone ring is non-aromatic may be connected to the parent structure ateither an aromatic ring position or at a non-aromatic ring position. Inone variation, a heteroaryl group having more than one ring where atleast one ring is non-aromatic is connected to the parent structure atan aromatic ring position. A heteroaryl group may be connected to theparent structure at a ring carbon atom or a ring heteroatom.

“Heteroarylene” as used herein refers to the same residues asheteroaryl, but having bivalency.

“Heterocycle”, “heterocyclic”, or “heterocyclyl” as used herein refersto a saturated or an unsaturated non-aromatic cyclic group having asingle ring or multiple condensed rings, and having from 1 to 14 annularcarbon atoms and from 1 to 6 annular heteroatoms, such as nitrogen,sulfur or oxygen, and the like. A heterocycle comprising more than onering may be fused, bridged or spiro, or any combination thereof, butexcludes heteroaryl. The heterocyclyl group may be optionallysubstituted independently with one or more substituents describedherein. Particular heterocyclyl groups are 3 to 14-membered rings having1 to 13 annular carbon atoms and 1 to 6 annular heteroatomsindependently selected from nitrogen, oxygen and sulfur, 3 to12-membered rings having 1 to 11 annular carbon atoms and 1 to 6 annularheteroatoms independently selected from nitrogen, oxygen and sulfur, 3to 10-membered rings having 1 to 9 annular carbon atoms and 1 to 4annular heteroatoms independently selected from nitrogen, oxygen andsulfur, 3 to 8-membered rings having 1 to 7 annular carbon atoms and 1to 4 annular heteroatoms independently selected from nitrogen, oxygenand sulfur, or 3 to 6-membered rings having 1 to 5 annular carbon atomsand 1 to 4 annular heteroatoms independently selected from nitrogen,oxygen and sulfur. In one variation, heterocyclyl includes monocyclic3-, 4-, 5-, 6- or 7-membered rings having from 1 to 2, 1 to 3, 1 to 4, 1to 5, or 1 to 6 annular carbon atoms and 1 to 2, 1 to 3, or 1 to 4annular heteroatoms independently selected from nitrogen, oxygen andsulfur. In another variation, heterocyclyl includes polycyclicnon-aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6annular heteroatoms independently selected from nitrogen, oxygen andsulfur.

“Heterocyclylene” as used herein refers to the same residues asheterocyclyl, but having bivalency.

“Halo” or “halogen” refers to elements of the Group 17 series havingatomic number 9 to 85. Preferred halo groups include the radicals offluorine, chlorine, bromine and iodine. Where a residue is substitutedwith more than one halogen, it may be referred to by using a prefixcorresponding to the number of halogen moieties attached, e.g.,dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkylsubstituted with two (“di”) or three (“tri”) halo groups, which may bebut are not necessarily the same halogen; thus 4-chloro-3-fluorophenylis within the scope of dihaloaryl. An alkyl group in which each hydrogenis replaced with a halo group is referred to as a “perhaloalkyl.” Apreferred perhaloalkyl group is trifluoromethyl (—CF₃). Similarly,“perhaloalkoxy” refers to an alkoxy group in which a halogen takes theplace of each H in the hydrocarbon making up the alkyl moiety of thealkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy(—OCF₃).

“Carbonyl” refers to the group C═O.

“Thiocarbonyl” refers to the group C═S.

“Oxo” refers to the moiety ═O.

“Optionally substituted” unless otherwise specified means that a groupmay be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or5) of the substituents listed for that group in which the substituentsmay be the same of different. In one embodiment, an optionallysubstituted group has one substituent. In another embodiment, anoptionally substituted group has two substituents. In anotherembodiment, an optionally substituted group has three substituents. Inanother embodiment, an optionally substituted group has foursubstituents. In some embodiments, an optionally substituted group has 1to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, or 2 to 5 substituents. Inone embodiment, an optionally substituted group is unsubstituted.

Unless clearly indicated otherwise, “an individual” as used hereinintends a mammal, including but not limited to a primate, human, bovine,horse, feline, canine, or rodent. In one variation, the individual is ahuman.

As used herein, “treatment” or “treating” is an approach for obtainingbeneficial or desired results including clinical results. For purposesof this disclosure, beneficial or desired results include, but are notlimited to, one or more of the following: decreasing one more symptomsresulting from the disease, diminishing the extent of the disease,stabilizing the disease (e.g., preventing or delaying the worsening ofthe disease), preventing or delaying the spread of the disease, delayingthe occurrence or recurrence of the disease, delay or slowing theprogression of the disease, ameliorating the disease state, providing aremission (whether partial or total) of the disease, decreasing the doseof one or more other medications required to treat the disease,enhancing effect of another medication, delaying the progression of thedisease, increasing the quality of life, and/or prolonging survival. Themethods of the present disclosure contemplate any one or more of theseaspects of treatment.

As used herein, the term “effective amount” intends such amount of acompound of the invention which should be effective in a giventherapeutic form. As is understood in the art, an effective amount maybe in one or more doses, i.e., a single dose or multiple doses may berequired to achieve the desired treatment endpoint. An effective amountmay be considered in the context of administering one or moretherapeutic agents (e.g., a compound, or pharmaceutically acceptablesalt thereof), and a single agent may be considered to be given in aneffective amount if, in conjunction with one or more other agents, adesirable or beneficial result may be or is achieved. Suitable doses ofany of the co-administered compounds may optionally be lowered due tothe combined action (e.g., additive or synergistic effects) of thecompounds.

A “therapeutically effective amount” refers to an amount of a compoundor salt thereof sufficient to produce a desired therapeutic outcome.

As used herein, “unit dosage form” refers to physically discrete units,suitable as unit dosages, each unit containing a predetermined quantityof active ingredient calculated to produce the desired therapeuticeffect in association with the required pharmaceutical carrier. Unitdosage forms may contain a single or a combination therapy.

As used herein, by “pharmaceutically acceptable” or “pharmacologicallyacceptable” is meant a material that is not biologically or otherwiseundesirable, e.g., the material may be incorporated into apharmaceutical composition administered to a patient without causing anysignificant undesirable biological effects or interacting in adeleterious manner with any of the other components of the compositionin which it is contained. Pharmaceutically acceptable carriers orexcipients have preferably met the required standards of toxicologicaland manufacturing testing and/or are included on the Inactive IngredientGuide prepared by the U.S. Food and Drug administration.

“Pharmaceutically acceptable salts” are those salts which retain atleast some of the biological activity of the free (non-salt) compoundand which can be administered as drugs or pharmaceuticals to anindividual. Such salts, for example, include: (1) acid addition salts,formed with inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like; or formedwith organic acids such as acetic acid, oxalic acid, propionic acid,succinic acid, maleic acid, tartaric acid and the like; (2) salts formedwhen an acidic proton present in the parent compound either is replacedby a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or analuminum ion; or coordinates with an organic base. Acceptable organicbases include ethanolamine, diethanolamine, triethanolamine and thelike. Acceptable inorganic bases include aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, andthe like. Pharmaceutically acceptable salts can be prepared in situ inthe manufacturing process, or by separately reacting a purified compoundof the present disclosure in its free acid or base form with a suitableorganic or inorganic base or acid, respectively, and isolating the saltthus formed during subsequent purification.

The term “excipient” as used herein means an inert or inactive substancethat may be used in the production of a drug or pharmaceutical, such asa tablet containing a compound of the present disclosure as an activeingredient. Various substances may be embraced by the term excipient,including without limitation any substance used as a binder,disintegrant, coating, compression/encapsulation aid, cream or lotion,lubricant, solutions for parenteral administration, materials forchewable tablets, sweetener or flavoring, suspending/gelling agent, orwet granulation agent. Binders include, e.g., carbomers, povidone,xanthan gum, etc.; coatings include, e.g., cellulose acetate phthalate,ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.;compression/encapsulation aids include, e.g., calcium carbonate,dextrose, fructose dc (dc=“directly compressible”), honey dc, lactose(anhydrate or monohydrate; optionally in combination with aspartame,cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.;disintegrants include, e.g., croscarmellose sodium, gellan gum, sodiumstarch glycolate, etc.; creams or lotions include, e.g., maltodextrin,carrageenans, etc.; lubricants include, e.g., magnesium stearate,stearic acid, sodium stearyl fumarate, etc.; materials for chewabletablets include, e.g., dextrose, fructose dc, lactose (monohydrate,optionally in combination with aspartame or cellulose), etc.;suspending/gelling agents include, e.g., carrageenan, sodium starchglycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame,dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulationagents include, e.g., calcium carbonate, maltodextrin, microcrystallinecellulose, etc.

It is understood that aspects and embodiments described herein as“comprising” include “consisting of” and “consisting essentially of”embodiments.

When a composition is described as “consisting essentially of” thelisted components, the composition contains the components expresslylisted, and may contain other components which do not substantiallyaffect the disease or condition being treated such as trace impurities.However, the composition either does not contain any other componentswhich do substantially affect the disease or condition being treatedother than those components expressly listed; or, if the compositiondoes contain extra components other than those listed whichsubstantially affect the disease or condition being treated, thecomposition does not contain a sufficient concentration or amount ofthose extra components to substantially affect the disease or conditionbeing treated. When a method is described as “consisting essentially of”the listed steps, the method contains the steps listed, and may containother steps that do not substantially affect the disease or conditionbeing treated, but the method does not contain any other steps whichsubstantially affect the disease or condition being treated other thanthose steps expressly listed.

When a moiety is indicated as substituted by “at least one” substituent,this also encompasses the disclosure of exactly one substituent.

Compounds

In one aspect, provided is a compound of formula (I):

or a pharmaceutically acceptable salt thereof;wherein:

-   -   X¹ and X², independently of each other, are CH or N;    -   Y¹ is selected from the group consisting of a bond, NR^(Y1), and        O; provided that when X¹ is N, then Y¹ is a bond;    -   R^(Y1) is hydrogen or C₁-C₆ alkyl;    -   Y² is selected from the group consisting of a bond, NR^(Y2), and        O; provided that when X² is N, then Y² is a bond;    -   R^(Y2) is hydrogen or C₁-C₆ alkyl;    -   m¹, m², n¹, n², p¹, p², q¹, and q², independently of each other,        are 0 or 1;    -   r and s, independently of each other, are 0, 1, or 2;    -   A¹ is selected from the group consisting of:        -   a substituent of formula (A¹-a)

-   -   -   -   wherein                -   * represents the attachment point to the remainder                    of the molecule;                -   Z¹ is selected from the group consisting of                    CR^(Z1-1)R^(Z1-2), NR^(Z1-2), O, S, and                    —CR^(Z1-1)═CR^(Z1-1)—;                -    wherein R^(Z1-1) is H or R¹⁴; and R^(Z1-2) is H or                    R¹⁴;                -   Z² is selected from the group consisting of                    CR^(Z2-1)R^(Z2-2), NR^(Z2-2), O, S, and                    —CR^(Z2-1)═CR^(Z2-1)—;                -    wherein R^(Z2-1) is H or R¹⁴; and R^(Z2-2) is H or                    R¹⁴;                -   Z³, independently at each occurrence, is C or N,                    provided that at least one Z³ is C;                -   R¹³ is hydrogen or R¹⁴, or R¹³ and R^(Z1-2) are                    taken together to form a double bond between the                    carbon atom bearing R¹³ and Z¹, or R¹³ and R^(Z2-2)                    are taken together to form a double bond between the                    carbon atom bearing R¹³ and Z²; and                -   x1 is 0, 1, 2, 3, or 4, provided than when one Z³ is                    N, then x1 is not 4;            -   C₆-C₁₀ aryl optionally substituted with one or more R¹⁴                substituents; and            -   5-10 membered heteroaryl optionally substituted with one                or more R¹⁴ substituents;

    -   R¹⁴ is selected, independently at each occurrence, from the        group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OH,        —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆ alkyl),        —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —NH(C₁-C₆        haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂,        —NR^(14-a)R^(14-b), —CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl),        —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),        —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆        haloalkyl)₂, —C(O)NR^(14-a)R^(14-b), —S(O)₂OH, —S(O)₂O(C₁-C₆        alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆        alkyl), —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,        —S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(14-a)R^(14-b), —OC(O)H,        —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H,        —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)C(O)H, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆        alkyl)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆        haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆        haloalkyl), —OS(O)₂(C₁-C₆ alkyl), —OS(O)₂(C₁-C₆ haloalkyl),        —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl),        —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆        haloalkyl)S(O)₂(C₁-C₆ haloalkyl);        -   wherein R^(14-a) and R^(14-b) are taken together with the            nitrogen atom which bears them to form a 3-10 membered            heterocycle;

    -   A² is selected from the group consisting of:        -   a substituent of formula (A²-a)

-   -   -   -   wherein                -   * represents the attachment point to the remainder                    of the molecule;                -   Z⁴ is selected from the group consisting of                    CR^(Z4-1)R^(Z4-2), NR^(Z4-2), O, S, and                    —CR^(Z4-1)═CR^(Z4-1)—;                -    wherein R^(Z4-1) is H or R¹⁶; and R^(Z4-2) is H or                    R¹⁶;                -   Z⁵ is selected from the group consisting of                    CR^(Z5-1)R^(Z5-2), NR^(Z5-2); O, S, and                    —CR^(Z5-1)═CR^(Z5-1)—;                -    wherein R^(Z5-1) is H or R¹⁶; and R^(Z5-2) is H or                    R¹⁶;                -   Z⁶, independently at each occurrence, is C or N,                    provided that at least one Z⁶ is C;                -   R¹⁵ is hydrogen or R¹⁶, or R¹⁵ and R^(Z4-2) are                    taken together to form a double bond between the                    carbon atom bearing R¹⁵ and Z⁴, or R¹⁵ and R^(Z5-2)                    are taken together to form a double bond between the                    carbon atom bearing R¹⁵ and Z⁵; and                -   x2 is 0, 1, 2, 3, or 4, provided than when one Z⁶ is                    N, then x2 is not 4;                    C₆-C₁₀ aryl optionally substituted with one or more                    R¹⁶ substituents; and                    5-10 membered heteroaryl optionally substituted with                    one or more R¹⁶ substituents;

    -   R¹⁶ is selected, independently at each occurrence, from the        group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OH,        —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆ alkyl),        —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —NH(C₁-C₆        haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂,        —NR^(16-a)R^(16-b), —CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl),        —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),        —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆        haloalkyl)₂, —C(O)NR^(16-a)R^(16-b), —S(O)₂OH, —S(O)₂O(C₁-C₆        alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆        alkyl), —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,        —S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(16-a)R^(16-b), —OC(O)H,        —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H,        —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)C(O)H, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆        alkyl)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆        haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆        haloalkyl), —OS(O)₂(C₁-C₆ alkyl), —OS(O)₂(C₁-C₆ haloalkyl),        —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl),        —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆        haloalkyl)S(O)₂(C₁-C₆ haloalkyl);        -   wherein R^(16-a) and R^(16-b) are taken together with the            nitrogen atom which bears them to form a 3-10 membered            heterocycle;

    -   R^(1a) and R^(1b) are independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, and halogen;

    -   R^(2a) and R^(2b) are independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, and halogen;

    -   when present, R^(3a) and R^(3b) are independently at each        occurrence selected from the group consisting of hydrogen, C₁-C₆        alkyl, and halogen;

    -   when present, R^(4a) and R^(4b) are independently at each        occurrence selected from the group consisting of hydrogen, C₁-C₆        alkyl, and halogen;

    -   or alternatively, R^(1a) and R^(2a) are taken together to form a        C₁-C₆ alkylene moiety;

    -   or alternatively, R^(1a) and an R^(3a) moiety, when present, are        taken together to form a C₁-C₆ alkylene moiety, and R^(1b) and        the R^(3b) in the geminal position to the R^(3a) taken together        with R^(1a), are both hydrogen;

    -   or alternatively, an R^(3a) moiety, when present, and an R^(4a)        moiety, when present, are taken together to form a C₁-C₆        alkylene moiety, and the R^(3b) in the geminal position to the        R^(3a) taken together with the R^(4a) moiety and the R^(4b) in        the geminal position to the R^(4a) taken together with the        R^(3a) moiety, are both hydrogen;

    -   when present, R^(5a) and R^(5b) are taken together to form an        oxo (═O) substituent or an imido (═NH) substituent, or        alternatively, R^(5a) and R^(5b) are both hydrogen;

    -   when present, R^(6a) is selected from the group consisting of        hydrogen, —OR^(6a-a), and —NR^(6a-b)R^(6a-c);

    -   when present, R^(6b) is hydrogen;

    -   or alternatively, R^(6a) and R^(6b) are taken together to form a        moiety selected from the group consisting of —O—CH₂—CH₂—,        —CH₂—O—CH₂—, —CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—, —CH₂—O—CH₂—CH₂—,        —CH₂—CH₂—O—CH₂—, —CH₂—CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—CH₂—,        —CH₂—O—CH₂—CH₂—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—CH₂—CH₂—O—CH₂—,        and —CH₂—CH₂—CH₂—CH₂—O—;

    -   when present, R^(7a) and R^(7b) are both hydrogen;

    -   when present, R^(8a) and R^(8b) are taken together to form an        oxo (═O) substituent, or alternatively, R^(8a) and R^(8b) are        both hydrogen;

    -   when present, R^(9a) and R^(9b) are taken together to form an        oxo (═O) substituent or an imido (═NH) substituent, or        alternatively, R^(9a) and R^(9b) are both hydrogen;

    -   when present, R^(10a) is selected from the group consisting of        hydrogen, —OR^(10a-a), and —NR^(10a-b)R^(10a-c);

    -   when present, R^(10b) is hydrogen;

    -   or alternatively, R^(10a) and R^(10b) are taken together to form        a moiety selected from the group consisting of —O—CH₂—CH₂—,        —CH₂—O—CH₂—, —CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—, —CH₂—O—CH₂—CH₂—,        —CH₂—CH₂—O—CH₂—, —CH₂—CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—CH₂—,        —CH₂—O—CH₂—CH₂—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—CH₂—CH₂—O—CH₂—,        and —CH₂—CH₂—CH₂—CH₂—O—;

    -   when present, R^(11a) and R^(11b) are both hydrogen;

    -   when present, R^(12a) and R^(12b) are taken together to form an        oxo (═O) substituent, or alternatively, R^(12a) and R^(12b) are        both hydrogen;

    -   R^(6a-a) is selected from the group consisting of hydrogen,        C₁-C₆ alkyl, and C₁-C₆ haloalkyl;

    -   R^(10a-a) is selected from the group consisting of hydrogen,        C₁-C₆ alkyl, and C₁-C₆ haloalkyl;

    -   or R^(6a-a) and R^(Y1) may be taken together to form a carbonyl        (C═O) moiety;

    -   or R^(10a-a) and R^(Y2) may be taken together to form a carbonyl        (C═O) moiety;

    -   R^(6a-b) and R^(6a-c), independently of each other, are selected        from the group consisting of hydrogen, C₁-C₆ alkyl, and C₁-C₆        haloalkyl; and

    -   R^(10a-b) and R^(10a-c), independently of each other, are        selected from the group consisting of hydrogen, C₁-C₆ alkyl, and        C₁-C₆ haloalkyl.

In some embodiments, the compound of formula (I) is a compound offormula (1-1):

or a pharmaceutically acceptable salt thereof;wherein:

A¹ is a substituent of formula (A¹-a)

A² is a substituent of formula (A²-a)

and wherein R^(Y1), R^(Y2), r, s, R^(Z1-1), R^(Z1-2), Z², R^(Z2-1),R^(Z2-2), Z³, x1, Z⁴, R^(Z4-1), R^(Z4-2), Z⁵, R^(Z5-1), R^(Z5-2), Z⁶,x2, R^(1a), R^(1b), R^(2a), R^(2b), R^(3a), R^(3b), R^(4a), R^(4b), R¹³,R¹⁴, R¹⁵, and R¹⁶ are as defined in compounds of formula (I).

In some embodiments of the compounds of formula (1-1), (A¹-a) isselected from the group consisting of:

In some embodiments of the compounds of formula (1-1), (A¹-a) is (A¹-b).

In some embodiments of the compounds of formula (1-1), (A¹-a) is (A¹-c).

In some embodiments of the compounds of formula (1-1), (A¹-a) is (A¹-d).

In some embodiments of the compounds of formula (1-1), (A¹-a) or (A¹-b)is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A¹-a) or (A¹-b) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A¹-a) or (A¹-b) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A¹-a) or (A¹-b) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (1-1), (A¹-a) or (A¹-c)is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A¹-a) or (A¹-c) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (1-1), (A²-a) isselected from the group consisting of:

In some embodiments of the compounds of formula (1-1), (A²-a) is (A²-b).

In some embodiments of the compounds of formula (1-1), (A²-a) is (A²-c).

In some embodiments of the compounds of formula (1-1), (A²-a) is (A²-d).

In some embodiments of the compounds of formula (1-1), (A²-a) or (A²-b)is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A²-a) or (A²-b) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A²-a) or (A²-b) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A²-a) or (A²-b) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (1-1), (A²-a) or (A²-c)is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A²-a) or (A²-c) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, the compound of formula (I) is a compound offormula (1-2):

or a pharmaceutically acceptable salt thereof;wherein:

A¹ is a substituent of formula (A¹-a)

A² is selected from the group consisting of:

-   -   a substituent of formula (A²-a)

-   -   C₆-C₁₀ aryl optionally substituted with one or more R¹⁶        substituents; and    -   5-10 membered heteroaryl optionally substituted with one or more        R¹⁶ substituents;

and wherein X², R^(Y1), Y², R^(Y2), r, s, Z¹, R^(Z1-1), R^(Z1-2), Z²,R^(Z2-1), R^(Z2-2), Z³, x1, Z⁴, R^(Z4-1), R^(Z4-2), Z⁵, R^(Z5-1),R^(Z5-2), Z⁶, x2, R^(1a), R^(1b), R^(2a), R^(2b), R^(3a), R^(3b),R^(4a), R^(4b), R^(9a), R^(9b), R^(10a), R^(10a-a), R^(10a-b),R^(10a-c), R^(10b), R¹³, R¹⁴, R¹⁵, and R¹⁶ are as defined in compoundsof formula (I).

In some embodiments of the compounds of formula (1-2), X² is CH. In someembodiments, r is 1 and s is 1.

In some embodiments of the compounds of formula (1-2), X² is N and Y² isa bond. In some embodiments, r is 1 and s is 1. In some embodiments, ris 0 and s is 2.

In some embodiments of the compounds of formula (1-2), (A¹-a) isselected from the group consisting of:

In some embodiments of the compounds of formula (1-2), (A¹-a) is (A¹-b).

In some embodiments of the compounds of formula (1-2), (A¹-a) is (A¹-c).

In some embodiments of the compounds of formula (1-2), (A¹-a) is (A¹-d).

In some embodiments of the compounds of formula (1-2), (A¹-a) or (A¹-b)is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A¹-a) or (A¹-b) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A¹-a) or (A¹-b) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A¹-a) or (A¹-b) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (1-2), (A¹-a) or (A¹-c)is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A¹-a) or (A¹-c) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (1-2):

-   -   q² is 1;    -   R^(9a) and R^(9b) are taken together to form an oxo (═O)        substituent or an imido (═NH) substituent, or alternatively,        R^(9a) and R^(9b) are both hydrogen;    -   R^(10a) is selected from the group consisting of hydrogen,        —OR^(10a-a), and —NR^(10a-b)R^(10a-c); R^(10b) is hydrogen;    -   or alternatively, R^(10a) and R^(10b) are taken together to form        a —CH₂—O—CH₂— moiety; and    -   A² is C₆-C₁₀ aryl optionally substituted with one or more R¹⁶        substituents, or 5-10 membered heteroaryl optionally substituted        with one or more R¹⁶ substituents.

In some embodiments of the compounds of formula (1-2):

-   -   R^(9a) and R^(9b) are taken together to form an oxo (═O)        substituent or an imido (═NH) substituent;    -   R^(10a) is selected from the group consisting of hydrogen,        —OR^(10a-a), and —NR^(10a-b)R^(10a-c);    -   R^(10b) is hydrogen; and    -   A² is C₆-C₁₀ aryl optionally substituted with one or more R¹⁶        substituents, or 5-10 membered heteroaryl optionally substituted        with one or more R¹⁶ substituents.

In some embodiments of the compounds of formula (1-2), R^(9a) and R^(9b)are taken together to form an oxo (═O) substituent. In some embodimentsof the compounds of formula (1-2), R^(9a) and R^(9b) are taken togetherto form an imido (═NH) substituent. In some embodiments, R^(10a) ishydrogen.

In some embodiments of the compounds of formula (1-2):

-   -   R^(9a) and R^(9b) are both hydrogen; and    -   R^(10a) and R^(10b) are taken together to form a —CH₂—O—CH₂—        moiety.

In some embodiments of the compounds of formula (1-2):

-   -   R^(9a) and R^(9b) are both hydrogen; and    -   R^(10a) and R^(10b) are both hydrogen.

In some embodiments of the compounds of formula (1-2):

-   -   X² is CH;    -   R^(Y1) is hydrogen or C₁-C₆ alkyl;    -   Y² is selected from the group consisting of NR^(Y2) and O;    -   R^(Y2) is hydrogen or C₁-C₆ alkyl;    -   q² is 1;    -   r and s, independently of each other, are 0, 1, or 2;    -   A¹ is a substituent of formula (A¹-a)

-   -   -   wherein            -   * represents the attachment point to the remainder of                the molecule;            -   Z¹ is selected from the group consisting of                CR^(Z1-1)R^(Z1-2), NR^(Z1-2), O, S, and                —CR^(Z1-1)═CR^(Z1-1)—,                -   wherein R^(Z1-1) is H or R¹⁴; and R^(Z1-2) is H or                    R¹⁴;            -   Z² is selected from the group consisting of                CR^(Z2-1)R^(Z2-2), NR^(Z2-2); O, S, and                —CR^(Z2-1)═CR^(Z2-1)—;                -   wherein R^(Z2-1) is H or R¹⁴; and R^(Z2-2) is H or                    R¹⁴;            -   Z³, independently at each occurrence, is C or N,                provided that at least one Z³ is C;            -   R¹³ is hydrogen or R¹⁴, or R¹³ and R^(Z1-2) are taken                together to form a double bond between the carbon atom                bearing R¹³ and Z¹, or R¹³ and R^(Z2-2) are taken                together to form a double bond between the carbon atom                bearing R¹³ and Z²; and            -   x1 is 1, 2, 3, or 4, and at least one R¹⁴ is halogen;

    -   R¹⁴ is selected, independently at each occurrence, from the        group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OH,        —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆ alkyl),        —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —NH(C₁-C₆        haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR¹⁴⁻        aR^(14-b), —CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆        haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆        haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆ haloalkyl)₂,        —C(O)NR^(14-a)R^(14-b), —S(O)₂OH, —S(O)₂O(C₁-C₆ alkyl),        —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl),        —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆        haloalkyl)₂, —S(O)₂NR^(14-a)R^(14-b), —OC(O)H, —OC(O)(C₁-C₆        alkyl), —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H, —N(H)C(O)(C₁-C₆        alkyl), —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)C(O)H,        —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆        haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆        haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆        haloalkyl), —OS(O)₂(C₁-C₆ alkyl), —OS(O)₂(C₁-C₆ haloalkyl),        —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl),        —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆        haloalkyl)S(O)₂(C₁-C₆ haloalkyl);        -   wherein R^(14-a) and R^(14-b) are taken together with the            nitrogen atom which bears them to form a 3-10 membered            heterocycle;

    -   A² is C₆-C₁₀ aryl substituted by at least one halogen        substituent and optionally further substituted with one or more        R¹⁶ substituents, or 5-10 membered heteroaryl substituted by at        least one halogen substituent and optionally further substituted        with one or more R¹⁶ substituents;

    -   R¹⁶ is selected, independently at each occurrence, from the        group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OH,        —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆ alkyl),        —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —NH(C₁-C₆        haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂,        —NR^(16-a)R^(16-b), —CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl),        —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),        —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆        haloalkyl)₂, —C(O)NR^(16-a)R^(16-b), —S(O)₂OH, —S(O)₂O(C₁-C₆        alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆        alkyl), —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,        —S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(16-a)R^(16-b), —OC(O)H,        —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H,        —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)C(O)H, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆        alkyl)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆        haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆        haloalkyl), —OS(O)₂(C₁-C₆ alkyl), —OS(O)₂(C₁-C₆ haloalkyl),        —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl),        —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆        haloalkyl)S(O)₂(C₁-C₆ haloalkyl);        -   wherein R^(16-a) and R^(16-b) are taken together with the            nitrogen atom which bears them to form a 3-10 membered            heterocycle;

    -   R^(1a) and R^(1b) are independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, and halogen;

    -   R^(2a) and R^(2b) are independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, and halogen;

    -   when present, R^(3a) and R^(3b) are independently at each        occurrence selected from the group consisting of hydrogen, C₁-C₆        alkyl, and halogen;

    -   when present, R^(4a) and R^(4b) are independently at each        occurrence selected from the group consisting of hydrogen, C₁-C₆        alkyl, and halogen;

    -   or alternatively, R^(1a) and R^(2a) are taken together to form a        C₁-C₆ alkylene moiety; or alternatively, R^(1a) and an R^(3a)        moiety, when present, are taken together to form a C₁-C₆        alkylene moiety, and R^(1b) and the R^(3b) in the geminal        position to the R^(3a) taken together with R^(1a), are both        hydrogen;

    -   or alternatively, an R^(3a) moiety, when present, and an R^(4a)        moiety, when present, are taken together to form a C₁-C₆        alkylene moiety, and the R^(3b) in the geminal position to the        R^(3a) taken together with the R^(4a) moiety and the R^(4b) in        the geminal position to the R^(4a) taken together with the        R^(3a) moiety, are both hydrogen;

    -   R^(9a) and R^(9b) are taken together to form an oxo (═O)        substituent or an imido (═NH) substituent, or alternatively,        R^(9a) and R^(9b) are both hydrogen;

    -   R^(10a) is hydrogen; and

    -   R^(10b) is hydrogen.

In some embodiments of the compounds of formula (1-2), R^(Y1) ishydrogen. In some embodiments of the compounds of formula (1-2), R^(Y1)is C₁-C₆ alkyl.

In some embodiments of the compounds of formula (1-2), Y² is NR^(Y2). Insome embodiments of the compounds of formula (1-2), R^(Y2) is hydrogen.In some embodiments of the compounds of formula (1-2), R^(Y2) is C₁-C₆alkyl.

In some embodiments of the compounds of formula (1-2), Y² is O.

In some embodiments of the compounds of formula (1-2), R^(1a) and R^(1b)are independently selected from the group consisting of hydrogen andC₁-C₆ alkyl. In some embodiments of the compounds of formula (1-2),R^(1a) and R^(1b) are both hydrogen.

In some embodiments of the compounds of formula (1-2), R^(2a) and R^(2b)are independently selected from the group consisting of hydrogen andC₁-C₆ alkyl. In some embodiments of the compounds of formula (1-2),R^(2a) and R^(2b) are both hydrogen.

In some embodiments of the compounds of formula (1-2), R^(1a) and R^(2a)are taken together to form a C₁-C₆ alkylene moiety.

In some embodiments of the compounds of formula (1-2), r is 1 and sis 1. In some embodiments, R^(3a) and R^(3b) are independently selectedfrom the group consisting of hydrogen and C₁-C₆ alkyl. In someembodiments, R^(3a) and R^(3b) are both hydrogen. In some embodiments,R^(4a) and R^(4b) are independently selected from the group consistingof hydrogen and C₁-C₆ alkyl. In some embodiments, R^(4a) and R^(4b) areboth hydrogen. In some embodiments, R^(1a) and R^(3a) are taken togetherto form a C₁-C₆ alkylene moiety, and R^(1b) and R^(3b) are bothhydrogen. In some embodiments, R^(3a) and R^(4a) are taken together toform a C₁-C₆ alkylene moiety, and R^(3b) and R^(4b) are both hydrogen.

In some embodiments of the compounds of formula (1-2), R^(9a) and R^(9b)are taken together to form an oxo (═O) substituent. In some embodimentsof the compounds of formula (1-2), R^(9a) and R^(9b) are taken togetherto form an imido (═NH) substituent.

In some embodiments of the compounds of formula (1-2), (A¹-a) isselected from the group consisting of:

In some embodiments of the compounds of formula (1-2), (A¹-a) is (A¹-b).

In some embodiments of the compounds of formula (1-2), (A¹-a) is (A¹-c).

In some embodiments of the compounds of formula (1-2), (A¹-a) is (A¹-d).

In some embodiments of the compounds of formula (1-2), (A¹-a) or (A¹-b)is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments x1 is 1, 2, 3, or 4, and at least one RHis halogen. In some embodiments, x1 is 1 and R¹⁴ is halogen. In someembodiments, x1 is 2 and at least one RH is halogen. In someembodiments, x1 is 3 and at least one R¹⁴ is halogen. In someembodiments, x1 is 4 and at least one R¹⁴ is halogen. In someembodiments, (A¹-a) or (A¹-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A¹-a) or (A¹-b) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments x1 is 1, 2, 3, or 4, and at least one R¹⁴is halogen. In some embodiments, x1 is 1 and RH is halogen. In someembodiments, x1 is 2 and at least one RH is halogen. In someembodiments, x1 is 3 and at least one R¹⁴ is halogen. In someembodiments, x1 is 4 and at least one R¹⁴ is halogen. In someembodiments, (A¹-a) or (A¹-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (1-2), (A¹-a) or (A¹-c)is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A¹-a) or (A¹-c) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (1-2), A² is C₆-C₁₀ arylsubstituted by at least one halogen substituent and optionally furthersubstituted with one or more R¹⁶ substituents, or 5-10 memberedheteroaryl substituted by at least one halogen substituent andoptionally further substituted with one or more R¹⁶ substituents.

In some embodiments of the compounds of formula (1-2), A² is C₆-C₁₀ aryloptionally substituted with one or more R¹⁶ substituents. In someembodiments, A² is C₆-C₁₀ aryl substituted by at least one halogensubstituent and optionally further substituted with one or more R¹⁶substituents. In some embodiments, A² is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A² is phenyl optionally substituted withone or more R¹⁶ substituents. In some embodiments, A² is phenylsubstituted by at least one halogen substituent and optionally furthersubstituted with one or more R¹⁶ substituents. In some embodiments, A²is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (1-2), A² is 5-10membered heteroaryl optionally substituted with one or more R¹⁶substituents. In some embodiments, A² is 5-10 membered heteroarylsubstituted by at least one halogen substituent and optionally furthersubstituted with one or more R¹⁶ substituents. In some embodiments, A²is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A² is pyridyl optionally substituted withone or more R¹⁶ substituents. In some embodiments, A² is pyridylsubstituted by at least one halogen substituent and optionally furthersubstituted with one or more R¹⁶ substituents. In some embodiments, A²is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (1-2):

-   -   q² is 0;    -   R^(9a) and R^(9b) are both hydrogen;    -   R^(10a) is —OR^(10a-a) or —NR^(10a-b)R^(10a-c); and    -   R^(10b) is hydrogen.

In some embodiments of the compounds of formula (1-2):

-   -   R^(10a) is-OR^(10a-a) or —NR^(10a-b)R^(10a-c); and    -   A² is a substituent of formula (A²-a)

In some embodiments of the compounds of formula (1-2), R^(10a) isOR^(10a-a).

In some embodiments of the compounds of formula (1-2), (A²-a) isselected from the group consisting of:

In some embodiments of the compounds of formula (1-2), (A²-a) is (A²-b).

In some embodiments of the compounds of formula (1-2), (A²-a) is (A²-c).

In some embodiments of the compounds of formula (1-2), (A²-a) is (A²-d).

In some embodiments of the compounds of formula (1-2), (A²-a) or (A²-b)is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A²-a) or (A²-b) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A²-a) or (A²-b) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A²-a) or (A²-b) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (1-2), (A²-a) or (A²-c)is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A²-a) or (A²-c) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A′-a) or (A′-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, the compound of formula (I) is a compound offormula (1-3):

or a pharmaceutically acceptable salt thereof;wherein:

-   -   A¹ is a substituent of formula (A¹-a)

-   -   A² is C₆-C₁₀ aryl optionally substituted with one or more R¹⁶        substituents; or 5-10 membered heteroaryl optionally substituted        with one or more R¹⁶ substituents;    -   and wherein X², R^(Y1), R^(Y2), r, s, Z¹, R^(Z1-1), R^(Z1-2),        Z², R^(Z2-1), R^(Z2-2), Z³, x1, R^(1a), R^(1b), R^(2a), R^(2b),        R^(3a), R^(3b), R^(4a), R^(4b), R^(9a), R^(9b), R^(10a),        R^(10a-a), R^(10a-b), R^(10a-c), R^(10b), R^(12a), R^(12b), R¹³,        R¹⁴, and R¹⁶ are as defined in compounds of formula (I).

In some embodiments of the compounds of formula (1-3), X² is CH. In someembodiments, r is 1 and s is 1.

In some embodiments of the compounds of formula (1-3), X² is N and Y² isa bond. In some embodiments, r is 1 and s is 1. In some embodiments, ris 0 and s is 2.

In some embodiments of the compounds of formula (1-3), (A¹-a) isselected from the group consisting of:

In some embodiments of the compounds of formula (1-3), (A¹-a) is (A¹-b).

In some embodiments of the compounds of formula (1-3), (A¹-a) is (A¹-c).

In some embodiments of the compounds of formula (1-3), (A¹-a) is (A¹-d).

In some embodiments of the compounds of formula (1-3), (A¹-a) or (A¹-b)is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A¹-a) or (A¹-b) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A¹-a) or (A¹-b) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A¹-a) or (A¹-b) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (1-3), (A¹-a) or (A¹-c)is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A¹-a) or (A¹-c) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (1-3):

-   -   R^(9a) and R^(9b) are taken together to form an oxo (═O)        substituent or an imido (═NH) substituent, or alternatively,        R^(9a) and R^(9b) are both hydrogen;    -   R^(10a) is selected from the group consisting of hydrogen,        —OR^(10a-a), and —NR^(10a-b)R^(10a-c);    -   R^(10b) is hydrogen; and    -   R^(12a) and R^(12b) are both hydrogen.

In some embodiments of the compounds of formula (1-3), R^(9a) and R^(9b)are taken together to form an oxo (═O) substituent. In some embodiments,R^(10a) is hydrogen. In some embodiments, R^(10a) is OR^(10a-a). In someembodiments, R^(10a) is NR^(10a-b)R^(10a-c).

In some embodiments of the compounds of formula (1-3), R^(9a) and R^(9b)are taken together to form an imido (═NH) substituent. In someembodiments, R^(10a) is hydrogen. In some embodiments, R^(10a) is—OR^(10a-a). In some embodiments, R^(10a) is NR^(10a-b)R^(10a-c).

In some embodiments of the compounds of formula (1-3), R^(9a) and R^(9b)are both hydrogen. In some embodiments, R^(10a) is hydrogen. In someembodiments, R^(10a) is OR^(10a-a). In some embodiments, R^(10a) isNR^(10a-b)R^(10a-c).

In some embodiments of the compounds of formula (1-3):

-   -   X² is CH or N;    -   R^(Y1) is hydrogen or C₁-C₆ alkyl;    -   Y² is selected from the group consisting of a bond, NR^(Y2), and        O; provided that when X² is N, then Y² is a bond;    -   R^(Y2) is hydrogen or C₁-C₆ alkyl;    -   r and s, independently of each other, are 0, 1, or 2;    -   A¹ is selected from the group consisting of:        -   a substituent of formula (A¹-a)

-   -   -   -   wherein                -   * represents the attachment point to the remainder                    of the molecule; Z¹ is selected from the group                    consisting of CR^(Z1-1)R^(Z1-2), NR^(Z1-2), O, S,                    and —CR^(Z1-1)═CR^(Z1-1)—,                -    wherein R^(Z1-1) is H or R¹⁴; and R^(Z1-2) is H or                    R¹⁴;                -   Z² is selected from the group consisting of                    CR^(Z2-1)R^(Z2-2), NR^(Z2-2); O, S, and                    —CR^(Z2-1)═CR^(Z2-1)—;                -    wherein R^(Z2-1) is H or R¹⁴; and R^(Z2-2) is H or                    R¹⁴;                -   Z³, independently at each occurrence, is C or N,                    provided that at least one Z³ is C;                -   R¹³ is hydrogen or R¹⁴, or R¹³ and R^(Z1-2) are                    taken together to form a double bond between the                    carbon atom bearing R¹³ and Z¹, or R¹³ and R^(Z2-2)                    are taken together to form a double bond between the                    carbon atom bearing R¹³ and Z²; and                -   x1 is 1, 2, 3, or 4, and at least one R¹⁴ is                    halogen;

    -   R¹⁴ is selected, independently at each occurrence, from the        group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OH,        —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆ alkyl),        —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —NH(C₁-C₆        haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂,        —NR^(14-a)R^(14-b); —CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl),        —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),        —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆        haloalkyl)₂, —C(O)NR^(14-a)R^(14-b); —S(O)₂OH, —S(O)₂O(C₁-C₆        alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆        alkyl), —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,        —S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(14-a)R^(14-b), —OC(O)H,        —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H,        —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)C(O)H, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆        alkyl)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆        haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆        haloalkyl), —OS(O)₂(C₁-C₆ alkyl), —OS(O)₂(C₁-C₆ haloalkyl),        —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl),        —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆        haloalkyl)S(O)₂(C₁-C₆ haloalkyl);        -   wherein R^(14-a) and R^(14-b) are taken together with the            nitrogen atom which bears them to form a 3-10 membered            heterocycle;

    -   A² is C₆-C₁₀ aryl substituted by at least one halogen        substituent and optionally further substituted with one or more        R¹⁶ substituents, or 5-10 membered heteroaryl substituted by at        least one halogen substituent and optionally further substituted        with one or more R¹⁶ substituents;

    -   R¹⁶ is selected, independently at each occurrence, from the        group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OH,        —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆ alkyl),        —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —NH(C₁-C₆        haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂,        —NR^(16-a)R^(16-b), —CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl),        —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),        —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆        haloalkyl)₂, —C(O)NR^(16-a)R^(16-b), —S(O)₂OH, —S(O)₂O(C₁-C₆        alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆        alkyl), —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,        —S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(16-a)R^(16-b), —OC(O)H,        —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H,        —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)C(O)H, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆        alkyl)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆        haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆        haloalkyl), —OS(O)₂(C₁-C₆ alkyl), —OS(O)₂(C₁-C₆ haloalkyl),        —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl),        —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆        haloalkyl)S(O)₂(C₁-C₆ haloalkyl);        -   wherein R^(16-a) and R^(16-b) are taken together with the            nitrogen atom which bears them to form a 3-10 membered            heterocycle;

    -   R^(1a) and R^(1b) are independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, and halogen;

    -   R^(2a) and R^(2b) are independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, and halogen;

    -   when present, R^(3a) and R^(3b) are independently at each        occurrence selected from the group consisting of hydrogen, C₁-C₆        alkyl, and halogen;

    -   when present, R^(4a) and R^(4b) are independently at each        occurrence selected from the group consisting of hydrogen, C₁-C₆        alkyl, and halogen;

    -   or alternatively, R^(1a) and R^(2a) are taken together to form a        C₁-C₆ alkylene moiety; or alternatively, R^(1a) and an R^(3a)        moiety, when present, are taken together to form a C₁-C₆        alkylene moiety, and R^(1b) and the R^(3b) in the geminal        position to the R^(3a) taken together with R^(1a), are both        hydrogen;

    -   or alternatively, an R^(3a) moiety, when present, and an R^(4a)        moiety, when present, are taken together to form a C₁-C₆        alkylene moiety, and the R^(3b) in the geminal position to the        R^(3a) taken together with the R^(4a) moiety and the R^(4b) in        the geminal position to the R^(4a) taken together with the        R^(3a) moiety, are both hydrogen;

    -   R^(9a) and R^(9b) are taken together to form an oxo (═O)        substituent or an imido (═NH) substituent, or alternatively,        R^(9a) and R^(9b) are both hydrogen;

    -   R^(10a) is selected from the group consisting of hydrogen,        —OR^(10a-a), and —NR^(10a-b)R^(10a-c);

    -   R^(10b) is hydrogen;

    -   R^(12a) and R^(12b) are taken together to form an oxo (═O)        substituent, or alternatively, R^(12a) and R^(12b) are both        hydrogen;

    -   R^(10a-a) is selected from the group consisting of hydrogen,        C₁-C₆ alkyl, and C₁-C₆ haloalkyl;

    -   or R^(10a-a) and R^(Y2) may be taken together to form a carbonyl        (C═O) moiety; and

    -   R^(10a-b) and R^(10a-c), independently of each other, are        selected from the group consisting of hydrogen, C₁-C₆ alkyl, and        C₁-C₆ haloalkyl.

In some embodiments of the compounds of formula (1-3), R^(Y1) ishydrogen. In some embodiments of the compounds of formula (1-3), R^(Y1)is C₁-C₆ alkyl.

In some embodiments of the compounds of formula (1-3), X² is CH and Y²is NR^(Y2). In some embodiments of the compounds of formula (1-2),R^(Y2) is hydrogen. In some embodiments of the compounds of formula(1-3), R^(Y2) is C₁-C₆ alkyl.

In some embodiments of the compounds of formula (1-3), X² is CH and Y²is O.

In some embodiments, X² is N and Y² is a bond.

In some embodiments of the compounds of formula (1-3), R^(1a) and R^(1b)are independently selected from the group consisting of hydrogen andC₁-C₆ alkyl. In some embodiments of the compounds of formula (1-3),R^(1a) and R^(1b) are both hydrogen.

In some embodiments of the compounds of formula (1-3), R^(2a) and R^(2b)are independently selected from the group consisting of hydrogen andC₁-C₆ alkyl. In some embodiments of the compounds of formula (1-3),R^(2a) and R^(2b) are both hydrogen.

In some embodiments of the compounds of formula (1-3), R^(1a) and R^(2a)are taken together to form a C₁-C₆ alkylene moiety.

In some embodiments of the compounds of formula (1-3), r is 1 and sis 1. In some embodiments, R^(3a) and R^(3b) are independently selectedfrom the group consisting of hydrogen and C₁-C₆ alkyl. In someembodiments, R^(3a) and R^(3b) are both hydrogen. In some embodiments,R^(4a) and R^(4b) are independently selected from the group consistingof hydrogen and C₁-C₆ alkyl. In some embodiments, R^(4a) and R^(4b) areboth hydrogen. In some embodiments, R^(1a) and R^(3a) are taken togetherto form a C₁-C₆ alkylene moiety, and R^(1b) and R^(3b) are bothhydrogen. In some embodiments, R^(3a) and R^(4a) are taken together toform a C₁-C₆ alkylene moiety, and R^(3b) and R^(4b) are both hydrogen.

In some embodiments of the compounds of formula (1-3), R^(9a) and R^(9b)are taken together to form an oxo (═O) substituent. In some embodimentsof the compounds of formula (1-3), R^(9a) and R^(9b) are taken togetherto form an imido (═NH) substituent. In some embodiments of the compoundsof formula (1-3), R^(9a) and R^(9b) are both hydrogen.

In some embodiments of the compounds of formula (1-3), R^(10a) ishydrogen and R^(10b) is hydrogen.

In some embodiments of the compounds of formula (1-3), R^(10a) is—OR^(10a-a) and R^(10b) is hydrogen. In some embodiments, R^(10a-a) isselected from the group consisting of hydrogen and C₁-C₆ alkyl. In someembodiments, R^(10a-a) is hydrogen. In some embodiments, R^(10a-a) isC₁-C₆ alkyl. In some embodiments, R^(10a-a) and R^(Y2) may be takentogether to form a carbonyl (C═O) moiety.

In some embodiments of the compounds of formula (1-3), R^(10a) is—NR^(10a-b)R^(10a-c) and R^(10b) is hydrogen. In some embodiments,R^(10a-b) and R^(10a-c), independently of each other, are selected fromthe group consisting of hydrogen and C₁-C₆ alkyl. In some embodiments,R^(10a-b) and R^(10a-c) are hydrogen. In some embodiments, R^(10a-b) andR^(10a-c) are C₁-C₆ alkyl.

In some embodiments of the compounds of formula (1-3):

-   -   X² is CH;    -   R^(Y1) is hydrogen;    -   Y² is NR^(Y2);    -   R^(Y2) is hydrogen;    -   R^(9a) and R^(9b) are both hydrogen;    -   R^(10a) is OR^(10a-a);    -   R^(10a-a) is hydrogen;    -   R^(10b) is hydrogen; and    -   R^(12a) and R^(12b) are both hydrogen.

In some embodiments of the compounds of formula (1-3):

-   -   X² is CH;    -   Y² is NR^(Y2);    -   R^(9a) and R^(9b) are both hydrogen;    -   R^(10a) is OR^(10a-a);    -   R^(12a) and R^(12b) are both hydrogen; and    -   R^(10a-a) and R^(Y2) are taken together to form a carbonyl (C═O)        moiety.

In some embodiments of the compounds of formula (1-3):

-   -   X² is CH;    -   R^(Y1) is hydrogen;    -   Y² is NR^(Y2);    -   R^(Y2) is hydrogen;    -   R^(9a) and R^(9b) are both hydrogen;    -   R^(10a) is OR^(10a-a);    -   R^(10b) is hydrogen;    -   R^(12a) and R^(12b) are both hydrogen; and    -   R^(10a-a) and R^(Y2) are taken together to form a carbonyl (C═O)        moiety.

In some embodiments of the compounds of formula (1-3):

-   -   X² is CH;    -   R^(Y1) is hydrogen;    -   Y² is NR^(Y2);    -   R^(Y2) is hydrogen;    -   R^(9a) and R^(9b) are both hydrogen;    -   R^(10a) is hydrogen;    -   R^(10b) is hydrogen; and    -   R^(12a) and R^(12b) are both hydrogen.

In some embodiments of the compounds of formula (1-3):

-   -   X² is N;    -   R^(Y1) is hydrogen;    -   Y² is a bond;    -   R^(9a) and R^(9b) are both hydrogen;    -   R^(10a) is —OR^(10a-a);    -   R^(10a-a) is hydrogen;    -   R^(10b) is hydrogen; and    -   R^(12a) and R^(12b) are both hydrogen.

In some embodiments of the compounds of formula (1-3):

-   -   X² is N;    -   R^(Y1) is hydrogen;    -   Y² is a bond;    -   R^(9a) and R^(9b) are both hydrogen;    -   R^(10a) is hydrogen;    -   R^(10b) is hydrogen; and    -   R^(12a) and R^(12b) are both hydrogen.

In some embodiments of the compounds of formula (1-3):

-   -   X² is CH;    -   R^(Y1) is hydrogen;    -   Y² is NR^(Y2);    -   R^(Y2) is hydrogen;    -   r and s are both 1;    -   R^(9a) and R^(9b) are both hydrogen;    -   R^(10a) is —OR^(10a-a);    -   R^(10a-a) is hydrogen;    -   R¹⁰ is hydrogen; and    -   R^(12a) and R^(12b) are both hydrogen.

In some embodiments of the compounds of formula (1-3):

-   -   X² is CH;    -   Y² is NR^(Y2);    -   r and s are both 1;    -   R^(9a) and R^(9b) are both hydrogen;    -   R^(10a) is —OR^(10a-a);    -   R^(12a) and R^(12b) are both hydrogen; and    -   R^(10a-a) and R^(Y2) are taken together to form a carbonyl (C═O)        moiety.

In some embodiments of the compounds of formula (1-3):

-   -   X² is CH;    -   R^(Y1) is hydrogen;    -   Y² is NR^(Y2);    -   R^(Y2) is hydrogen;    -   r and s are both 1;    -   R^(9a) and R^(9b) are both hydrogen;    -   R^(10a) is —OR^(10a-a);    -   R^(10b) is hydrogen;    -   R^(12a) and R^(12b) are both hydrogen; and    -   R^(10a-a) and R^(Y2) are taken together to form a carbonyl (C═O)        moiety.

In some embodiments of the compounds of formula (1-3):

-   -   X² is CH;    -   R^(Y1) is hydrogen;    -   Y² is NR^(Y2);    -   R^(Y2) is hydrogen;    -   r and s are both 1;    -   R^(9a) and R^(9b) are both hydrogen;    -   R^(10a) is hydrogen;    -   R^(10b) is hydrogen; and    -   R^(12a) and R^(12b) are both hydrogen.

In some embodiments of the compounds of formula (1-3):

-   -   X² is N;    -   R^(Y1) is hydrogen;    -   Y² is a bond;    -   r and s are both 1;    -   R^(9a) and R^(9b) are both hydrogen;    -   R^(10a) is —OR^(10a-a);    -   R^(10a-a) is hydrogen;    -   R^(10b) is hydrogen; and    -   R^(12a) and R^(12b) are both hydrogen.

In some embodiments of the compounds of formula (1-3):

-   -   X² is N;    -   R^(Y1) is hydrogen;    -   Y² is a bond;    -   r and s are both 1;    -   R^(9a) and R^(9b) are both hydrogen;    -   R^(10a) is hydrogen;    -   R^(10b) is hydrogen; and    -   R^(12a) and R^(12b) are both hydrogen.

R^(12a) and R^(12b) are both hydrogen. In some embodiments of thecompounds of formula (1-3), A² is C₆-C₁₀ aryl substituted by at leastone halogen substituent and optionally further substituted with one ormore R¹⁶ substituents, or 5-10 membered heteroaryl substituted by atleast one halogen substituent and optionally further substituted withone or more R¹⁶ substituents.

In some embodiments of the compounds of formula (1-3), A² is C₆-C₁₀ aryloptionally substituted with one or more R¹⁶ substituents. In someembodiments, A² is C₆-C₁₀ aryl substituted by at least one halogensubstituent and optionally further substituted with one or more R¹⁶substituents. In some embodiments, A² is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A² is phenyl optionally substituted withone or more R¹⁶ substituents. In some embodiments, A² is phenylsubstituted by at least one halogen substituent and optionally furthersubstituted with one or more R¹⁶ substituents. In some embodiments, A²is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A² is 5-10 membered heteroaryl optionallysubstituted with one or more R¹⁶ substituents. In some embodiments, A²is 5-10 membered heteroaryl substituted by at least one halogensubstituent and optionally further substituted with one or more R¹⁶substituents. In some embodiments, A² is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A² is pyridyl optionally substituted withone or more R¹⁶ substituents. In some embodiments, A² is pyridylsubstituted by at least one halogen substituent and optionally furthersubstituted with one or more R¹⁶ substituents. In some embodiments, A²is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, the compound of formula (I) is a compound offormula (1-4):

or a pharmaceutically acceptable salt thereof;wherein:

-   -   A¹ is a substituent of formula (A¹-a)

-   -   A² is C₆-C₁₀ aryl optionally substituted with one or more R¹⁶        substituents; or 5-10 membered heteroaryl optionally substituted        with one or more R¹⁶ substituents;    -   R^(11a) and R^(11b) are both hydrogen;    -   R^(12a) and R^(12b) are both hydrogen;

and wherein X², R^(Y1), Y², R^(Y2), r, s, A¹, Z¹, R^(Z1-1), R^(Z1-2),Z², R^(Z2-1), R^(Z2-2), Z³, x1, R^(1a), R^(1b), R^(2a), R^(2b), R^(3a),R^(3b), R^(4a), R^(4b), R¹³, R¹⁴, and R¹⁶ are as defined in compounds offormula (I).

In some embodiments of the compounds of formula (1-4), X² is CH. In someembodiments, r is 1 and s is 1.

In some embodiments of the compounds of formula (1-4), X² is N and Y² isa bond. In some embodiments, r is 1 and s is 1. In some embodiments, ris 0 and s is 2.

In some embodiments of the compounds of formula (1-4), (A¹-a) isselected from the group consisting of:

In some embodiments of the compounds of formula (1-4), (A¹-a) is (A¹-b).

In some embodiments of the compounds of formula (1-4), (A¹-a) is (A¹-c).

In some embodiments of the compounds of formula (1-4), (A¹-a) is (A¹-d).

In some embodiments of the compounds of formula (1-4), (A¹-a) or (A¹-b)is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A¹-a) or (A¹-b) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A¹-a) or (A¹-b) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A¹-a) or (A¹-b) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (1-4), (A¹-a) or (A¹-c)is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A¹-a) or (A¹-c) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (1-4), A² is C₆-C₁₀ aryloptionally substituted with one or more R¹⁶ substituents. In someembodiments, A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A² is phenyl optionally substituted withone or more R¹⁶ substituents. In some embodiments, A² is selected fromthe group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (1-4), A² is 5-10membered heteroaryl optionally substituted with one or more R¹⁶substituents. In some embodiments, A² is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A² is pyridyl optionally substituted withone or more R¹⁶ substituents. In some embodiments, A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, the compound of formula (I) is a compound offormula (2-2):

or a pharmaceutically acceptable salt thereof;wherein:

A¹ is selected from the group consisting of:

-   -   a substituent of formula (A¹-a)

-   -   C₆-C₁₀ aryl optionally substituted with one or more R¹⁴        substituents; and    -   5-10 membered heteroaryl optionally substituted with one or more        R¹⁴ substituents;

A² is selected from the group consisting of:

-   -   a substituent of formula (A²-a)

-   -   C₆-C₁₀ aryl optionally substituted with one or more R¹⁶        substituents; and    -   5-10 membered heteroaryl optionally substituted with one or more        R¹⁶ substituents;

and wherein X¹, X², Y¹, R^(Y1), Y², R^(Y2), q¹, q², r, s, Z¹, R^(Z1-1),R^(Z1-2), Z², R^(Z2-1), R^(Z2-2), Z³, x1, Z⁴, R^(Z4-1), R^(Z4-2), Z⁵,R^(Z5-1), R^(Z5-2), Z⁶, x2, R^(1a), R^(1b), R^(2a), R^(2b), R^(3a),R^(3b), R^(4a), R^(4b), R^(5a), R^(5b), R^(6a), R^(6a-a), R^(6a-b),R^(6a-c), R^(6b), R^(9a), R^(9b), R^(10a), R^(10a-a), R^(10a-b),R^(10a-c), R^(10b), R¹³, R¹⁴, R¹⁵, and R¹⁶ are as defined in compoundsof formula (I).

In some embodiments of the compounds of formula (2-2), X¹ is CH and X²is CH. In some embodiments, r is 1 and s is 1.

In some embodiments of the compounds of formula (2-2), X¹ is CH, X² is Nand Y² is a bond. In some embodiments, r is 1 and s is 1. In someembodiments, r is 0 and s is 2.

In some embodiments of the compounds of formula (2-2), X¹ is N, Y¹ is abond, and X² is CH. In some embodiments, r is 1 and s is 1. In someembodiments, r is 0 and s is 2.

In some embodiments of the compounds of formula (2-2), X¹ is N, Y¹ is abond, X² is N and Y² is a bond. In some embodiments, r is 1 and s is 1.In some embodiments, r is 0 and s is 2.

In some embodiments of the compounds of formula (2-2):

-   -   q¹ is 1;    -   A¹ is selected C₆-C₁₀ aryl optionally substituted with one or        more R¹⁴ substituents; or 5-10 membered heteroaryl optionally        substituted with one or more R¹⁴ substituents;    -   A² is selected from the group consisting of:        -   a substituent of formula (A²-a)

-   -   -   C₆-C₁₀ aryl optionally substituted with one or more R¹⁶            substituents; and        -   5-10 membered heteroaryl optionally substituted with one or            more R¹⁶ substituents;

    -   R^(5a) and R^(5b) are taken together to form an oxo (═O)        substituent or an imido (═NH) substituent, or alternatively,        R^(5a) and R^(5b) are both hydrogen;

    -   R^(6a) is selected from the group consisting of hydrogen,        —OR^(6a-a), and —NR^(6a-b)R^(6a-c);

    -   R^(6b) is hydrogen;

    -   or alternatively, R^(6a) and R^(6b) are taken together to form a        —CH₂—O—CH₂— moiety;

    -   R^(9a) and R^(9b) are both hydrogen;

    -   R^(10a) is selected from the group consisting of OR^(10a-a) and        NR^(10a-b)R^(10a-c); and,

    -   R^(10b) is hydrogen;

    -   or alternatively, R^(10a) and R^(10b) are taken together to form        a —CH₂—O—CH₂— moiety.

In some embodiments of the compounds of formula (2-2):

-   -   R^(5a) and R^(5b) are taken together to form an oxo (═O)        substituent;    -   R^(6a) is hydrogen;    -   R^(6b) is hydrogen;    -   R^(9a) and R^(9b) are both hydrogen;    -   R^(10a) is selected from the group consisting of OR^(10a-a), and        NR^(10a-b)R^(10a-c); and    -   R^(10b) is hydrogen;    -   or alternatively, R^(10a) and R^(10b) are taken together to form        a —CH₂—O—CH₂— moiety.

In some embodiments of the compounds of formula (2-2):

-   -   q² is 1;    -   A² is C₆-C₁₀ aryl optionally substituted with one or more R¹⁶        substituents; or 5-10 membered heteroaryl optionally substituted        with one or more R¹⁶ substituents; and    -   R^(10a) and R^(10b) are taken together to form a —CH₂—O—CH₂—        moiety.

In some embodiments of the compounds of formula (2-2), A² is C₆-C₁₀ aryloptionally substituted with one or more R¹⁶ substituents. In someembodiments, A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A² is phenyl optionally substituted withone or more R¹⁶ substituents. In some embodiments, A² is selected fromthe group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (2-2), A² is 5-10membered heteroaryl optionally substituted with one or more R¹⁶substituents. In some embodiments, A² is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A² is pyridyl optionally substituted withone or more R¹⁶ substituents. In some embodiments, A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (2-2):

-   -   q² is 0;    -   A² is a substituent of formula (A²-a)

-   -   R^(10a) is —OR^(10a-a) and    -   R^(10b) is hydrogen.

In some embodiments of the compounds of formula (2-2), (A²-a) isselected from the group consisting of:

In some embodiments of the compounds of formula (2-2), (A²-a) is (A²-b).

In some embodiments of the compounds of formula (2-2), (A²-a) is (A²-c).

In some embodiments of the compounds of formula (2-2), (A²-a) is (A²-d).

In some embodiments of the compounds of formula (2-2), (A²-a) or (A²-b)is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A²-a) or (A²-b) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A²-a) or (A²-b) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A²-a) or (A²-b) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (2-2), (A²-a) or (A²-c)is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A²-a) or (A²-c) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (2-2):

-   -   R^(5a) and R^(5b) are both hydrogen;    -   R^(ha) and R^(bb) are taken together to form a —CH₂—O—CH₂—        moiety;    -   R^(10a) is selected from the group consisting of OR^(10a-a) and        NR^(10a-b)R^(10a-c); and,    -   R^(10b) is hydrogen;    -   or alternatively, R^(10a) and R^(10b) are taken together to form        a —CH₂—O—CH₂— moiety.

In some embodiments of the compounds of formula (2-2):

-   -   q² is 1;    -   A² is C₆-C₁₀ aryl optionally substituted with one or more R¹⁶        substituents; or 5-10 membered heteroaryl optionally substituted        with one or more R¹⁶ substituents; and    -   R^(10a) and R^(10b) are taken together to form a —CH₂—O—CH₂—        moiety.

In some embodiments of the compounds of formula (2-2), A² is C₆-C₁₀ aryloptionally substituted with one or more R¹⁶ substituents. In someembodiments, A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A² is phenyl optionally substituted withone or more R¹⁶ substituents. In some embodiments, A² is selected fromthe group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (2-2), A² is 5-10membered heteroaryl optionally substituted with one or more R¹⁶substituents. In some embodiments, A² is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A² is pyridyl optionally substituted withone or more R¹⁶ substituents. In some embodiments, A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (2-2):

-   -   q² is 0;    -   A² is a substituent of formula (A²-a)

-   -   R^(10a) is —OR^(10a-a) and    -   R^(10b) is hydrogen.

In some embodiments of the compounds of formula (2-2), (A²-a) isselected from the group consisting of:

In some embodiments of the compounds of formula (2-2), (A²-a) is (A²-b).

In some embodiments of the compounds of formula (2-2), (A²-a) is (A²-c).

In some embodiments of the compounds of formula (2-2), (A²-a) is (A²-d).

In some embodiments of the compounds of formula (2-2), (A²-a) or (A²-b)is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A²-a) or (A²-b) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A²-a) or (A²-b) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A²-a) or (A²-b) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (2-2), (A²-a) or (A²-c)is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A²-a) or (A²-c) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (2-2), A¹ is C₆-C₁₀ aryloptionally substituted with one or more R¹⁴ substituents. In someembodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹ is phenyl optionally substituted withone or more R¹⁴ substituents. In some embodiments, A¹ is selected fromthe group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (2-2), A¹ is 5-10membered heteroaryl optionally substituted with one or more R¹⁴substituents. In some embodiments, A¹ is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹ is pyridyl optionally substituted withone or more RH substituents. In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is wherein the * represents the attachment pointto the remainder of the molecule; and (A²-a) or (A²-b) is selected fromthe group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, the compound of formula (I) is a compound offormula (2-3):

or a pharmaceutically acceptable salt thereof;wherein:

-   -   A¹ is selected from the group consisting of:        -   a substituent of formula (A¹-a)

-   -   -   C₆-C₁₀ aryl optionally substituted with one or more R¹⁴            substituents; and        -   5-10 membered heteroaryl optionally substituted with one or            more R¹⁴ substituents;

    -   A² is C₆-C₁₀ aryl optionally substituted with one or more R¹⁶        substituents; or 5-10 membered heteroaryl optionally substituted        with one or more R¹⁶ substituents;

and wherein X¹, X², Y¹, R^(Y1), R^(Y2), q¹, r, s, Z¹, R^(Z1-1),R^(Z1-2), Z², R^(Z2-1), R^(Z2-2), Z³, x1, R^(1a), R^(1b), R^(2a),R^(2b), R^(3a), R^(3b), R^(4a), R^(4b), R^(5a), R^(5b), R^(6a),R^(6a-a), R^(6a-b), R^(6a-c), R^(6b), R^(9a), R^(9b), R^(10a),R^(10a-a), R^(10a-b), R^(10a-c), R^(10b), R^(12a), R^(12b), R¹³, R¹⁴,and R¹⁶ are as defined in compounds of formula (I).

In some embodiments of the compounds of formula (2-3), X¹ is CH and X²is CH. In some embodiments, r is 1 and s is 1.

In some embodiments of the compounds of formula (2-3), X¹ is CH, X² is Nand Y² is a bond. In some embodiments, r is 1 and s is 1. In someembodiments, r is 0 and s is 2.

In some embodiments of the compounds of formula (2-3), X¹ is N, Y¹ is abond, and X² is CH. In some embodiments, r is 1 and s is 1. In someembodiments, r is 0 and s is 2.

In some embodiments of the compounds of formula (2-3), X¹ is N, Y¹ is abond, X² is N and Y² is a bond. In some embodiments, r is 1 and s is 1.In some embodiments, r is 0 and s is 2.

In some embodiments of the compounds of formula (2-3):

-   -   q¹ is 1;    -   A¹ is selected C₆-C₁₀ aryl optionally substituted with one or        more R¹⁴ substituents; or 5-10 membered heteroaryl optionally        substituted with one or more R¹⁴ substituents;    -   A² is C₆-C₁₀ aryl optionally substituted with one or more R¹⁶        substituents; or 5-10 membered heteroaryl optionally substituted        with one or more R¹⁶ substituents;    -   R^(5a) and R^(5b) are taken together to form an oxo (═O)        substituent or an imido (═NH) substituent, or alternatively,        R^(5a) and R^(5b) are both hydrogen;    -   R^(6a-c); and    -   R^(6a) is selected from the group consisting of hydrogen,        —OR^(6a-a), and —NR^(6a-b)R^(6a-c); and    -   R^(6b) is hydrogen;    -   or alternatively, R^(6a) and R^(6b) are taken together to form a        —CH₂—O—CH₂— moiety.

In some embodiments of the compounds of formula (2-3):

-   -   R^(5a) and R^(5b) are taken together to form an oxo (═O)        substituent;    -   R^(6a) is hydrogen; and    -   R^(6b) is hydrogen.

In some embodiments of the compounds of formula (2-3):

-   -   R^(5a) and R^(5b) are both hydrogen; and    -   R^(6a) and R^(6b) are taken together to form a —CH₂—O—CH₂—        moiety.

In some embodiments of the compounds of formula (2-3):

-   -   X¹ and X², independently of each other, are CH or N; provided        that at least one of X¹ and X² is CH;    -   Y¹ is selected from the group consisting of a bond, NR^(Y1), and        O; provided that when X¹ is N, then Y¹ is a bond;    -   R^(Y1) is hydrogen or C₁-C₆ alkyl;    -   Y² is selected from the group consisting of a bond, NR^(Y2), and        O; provided that when X² is N, then Y² is a bond;    -   R^(Y2) is hydrogen or C₁-C₆ alkyl;    -   q¹ is 1;    -   r and s, independently of each other, are 0, 1, or 2;    -   A¹ is C₆-C₁₀ aryl substituted by at least one halogen        substituent and optionally further substituted with one or more        R¹⁴ substituents, or 5-10 membered heteroaryl substituted by at        least one halogen substituent and optionally further substituted        with one or more R¹⁴ substituents;    -   R¹⁴ is selected, independently at each occurrence, from the        group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OH,        —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆ alkyl),        —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —NH(C₁-C₆        haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂,        —NR^(14-a)R^(14-b), —CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl),        —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),        —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆        haloalkyl)₂, —C(O)NR^(14-a)R^(14-b), —S(O)₂OH, —S(O)₂O(C₁-C₆        alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆        alkyl), —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,        —S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(14-a)R^(14-b), —OC(O)H,        —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H,        —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)C(O)H, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆        alkyl)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆        haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆        haloalkyl), —OS(O)₂(C₁-C₆ alkyl), —OS(O)₂(C₁-C₆ haloalkyl),        —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl),        —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆        haloalkyl)S(O)₂(C₁-C₆ haloalkyl);        -   wherein R^(14-a) and R^(14-b) are taken together with the            nitrogen atom which bears them to form a 3-10 membered            heterocycle;    -   A² is C₆-C₁₀ aryl substituted by at least one halogen        substituent and optionally further substituted with one or more        R¹⁶ substituents, or 5-10 membered heteroaryl substituted by at        least one halogen substituent and optionally further substituted        with one or more R¹⁶ substituents;    -   R¹⁶ is selected, independently at each occurrence, from the        group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OH,        —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆ alkyl),        —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —NH(C₁-C₆        haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂,        —NR^(16-a)R^(16-b), —CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl),        —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),        —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆        haloalkyl)₂, —C(O)NR^(16-a)R^(16-b), —S(O)₂OH, —S(O)₂O(C₁-C₆        alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆        alkyl), —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,        —S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(16-a)R^(16-b), —OC(O)H,        —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H,        —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)C(O)H, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆        alkyl)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆        haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆        haloalkyl), —OS(O)₂(C₁-C₆ alkyl), —OS(O)₂(C₁-C₆ haloalkyl),        —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl),        —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆        haloalkyl)S(O)₂(C₁-C₆ haloalkyl);        -   wherein R^(16-a) and R^(16-b) are taken together with the            nitrogen atom which bears them to form a 3-10 membered            heterocycle;    -   R^(1a) and R^(1b) are independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, and halogen;    -   R^(2a) and R^(2b) are independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, and halogen;    -   when present, R^(3a) and R^(3b) are independently at each        occurrence selected from the group consisting of hydrogen, C₁-C₆        alkyl, and halogen;    -   when present, R^(4a) and R^(4b) are independently at each        occurrence selected from the group consisting of hydrogen, C₁-C₆        alkyl, and halogen;    -   or alternatively, R^(1a) and R^(2a) are taken together to form a        C₁-C₆ alkylene moiety; or alternatively, R^(1a) and an R^(3a)        moiety, when present, are taken together to form a C₁-C₆        alkylene moiety, and R^(1b) and the R^(2b) in the geminal        position to the R^(1a) taken together with R^(1a), are both        hydrogen;    -   or alternatively, an R^(3a) moiety, when present, and an R^(4a)        moiety, when present, are taken together to form a C₁-C₆        alkylene moiety, and the R^(3b) in the geminal position to the        R^(3a) taken together with the R^(4a) moiety and the R^(4b) in        the geminal position to the R^(4a) taken together with the        R^(3a) moiety, are both hydrogen;    -   R^(5a) and R^(5b) are taken together to form an oxo (═O)        substituent or an imido (═NH) substituent;    -   R^(6a) is hydrogen;    -   R^(6b) is hydrogen;    -   R^(9a) and R^(9b) are taken together to form an oxo (═O)        substituent or an imido (═NH) substituent, or alternatively,        R^(9a) and R^(9b) are both hydrogen;    -   R^(10a) is selected from the group consisting of hydrogen,        —OR^(10a-a), and —NR^(10a-b)R^(10a-c);    -   R^(10b) is hydrogen;    -   R^(12a) and R^(12b) are taken together to form an oxo (═O)        substituent, or alternatively, R^(12a) and R^(12b) are both        hydrogen; R^(10a-a) is selected from the group consisting of        hydrogen, C₁-C₆ alkyl, and C₁-C₆ haloalkyl;    -   or R^(10a-a) and R^(Y2) may be taken together to form a carbonyl        (C═O) moiety;    -   R^(10a-b) and R^(10a-c), independently of each other, are        selected from the group consisting of hydrogen, C₁-C₆ alkyl, and        C₁-C₆ haloalkyl; and    -   provided that when X² is N, then:    -   A¹ is C₆-C₁₀ aryl substituted by at least two halogen        substituents and optionally further substituted with one or more        R¹⁴ substituents, or 5-10 membered heteroaryl substituted by at        least two halogen substituents and optionally further        substituted with one or more R¹⁴ substituents; and    -   A² is C₆-C₁₀ aryl substituted by at least two halogen        substituents and optionally further substituted with one or more        R¹⁶ substituents, or 5-10 membered heteroaryl substituted by at        least two halogen substituents and optionally further        substituted with one or more R¹⁶ substituents.

In some embodiments of the compounds of formula (2-3), R^(1a) and R^(1b)are independently selected from the group consisting of hydrogen andC₁-C₆ alkyl. In some embodiments of the compounds of formula (2-3),R^(1a) and R^(1b) are both hydrogen.

In some embodiments of the compounds of formula (2-3), R^(2a) and R^(2b)are independently selected from the group consisting of hydrogen andC₁-C₆ alkyl. In some embodiments of the compounds of formula (2-3),R^(2a) and R^(2b) are both hydrogen.

In some embodiments of the compounds of formula (2-3), R^(1a) and R^(2a)are taken together to form a C₁-C₆ alkylene moiety

In some embodiments of the compounds of formula (2-3), r is 1 and sis 1. In some embodiments, R^(3a) and R^(3b) are independently selectedfrom the group consisting of hydrogen and C₁-C₆ alkyl. In someembodiments, R^(3a) and R^(3b) are both hydrogen. In some embodiments,R^(4a) and R^(4b) are independently selected from the group consistingof hydrogen and C₁-C₆ alkyl. In some embodiments, R^(4a) and R^(4b) areboth hydrogen. In some embodiments, R^(1a) and R^(3a) are taken togetherto form a C₁-C₆ alkylene moiety, and R^(1b) and R^(3b) are bothhydrogen. In some embodiments, R^(3a) and R^(4a) are taken together toform a C₁-C₆ alkylene moiety, and R^(3b) and R^(4b) are both hydrogen.

In some embodiments of the compounds of formula (2-3):

-   -   X¹ is CH;    -   X² is CH;    -   Y¹ is selected from the group consisting of NR^(Y1) and O;    -   R^(Y1) is hydrogen or C₁-C₆ alkyl;    -   Y² is selected from the group consisting of NR^(Y2) and O;    -   R^(Y2) is hydrogen or C₁-C₆ alkyl;    -   q¹ and q² are each 1; and    -   r and s are both 1.

In some embodiments of the compounds of formula (2-3):

-   -   X¹ is CH;    -   X² is CH;    -   Y¹ is NR^(Y1);    -   R^(Y1) is hydrogen;    -   Y² is NR^(Y2);    -   R^(Y2) is hydrogen;    -   q1 is 1; and    -   r and s are both 1.

In some embodiments of the compounds of formula (2-3), R^(9a) and R^(9b)are taken together to form an oxo (═O) substituent. In some embodimentsof the compounds of formula (2-3), R^(9a) and R^(9b) are taken togetherto form an imido (═NH) substituent. In some embodiments of the compoundsof formula (2-3), R^(9a) and R^(9b) are both hydrogen.

In some embodiments of the compounds of formula (2-3), R^(10a) ishydrogen and R^(10b) is hydrogen.

In some embodiments of the compounds of formula (2-3), R^(10a) is—OR^(10a-a) and R^(10b) is hydrogen. In some embodiments, R^(10a-a) isselected from the group consisting of hydrogen and C₁-C₆ alkyl. In someembodiments, R^(10a-a) is hydrogen. In some embodiments, R^(10a-a) isC₁-C₆ alkyl. In some embodiments, R^(10a-a) and R^(Y2) may be takentogether to form a carbonyl (C═O) moiety.

In some embodiments of the compounds of formula (2-3), R^(10a) is—NR^(10a-b)R^(10a-c) and R^(10b) is hydrogen. In some embodiments,R^(10a-b) and R^(10a-c), independently of each other, are selected fromthe group consisting of hydrogen and C₁-C₆ alkyl. In some embodiments,R^(10a-b) and R^(10a-c) are hydrogen. In some embodiments, R^(10a-b) andR^(10a-c) are C₁-C₆ alkyl.

In some embodiments of the compounds of formula (2-3), A¹ is C₆-C₁₀ arylsubstituted by at least one halogen substituent and optionally furthersubstituted with one or more R¹⁴ substituents, or 5-10 memberedheteroaryl substituted by at least one halogen substituent andoptionally further substituted with one or more R¹⁴ substituents.

In some embodiments of the compounds of formula (2-3), A¹ is C₆-C₁₀ aryloptionally substituted with one or more R¹⁴ substituents. In someembodiments, A¹ is C₆-C₁₀ aryl substituted by at least one halogensubstituent and optionally further substituted with one or more R¹⁴substituents. In some embodiments, A¹ is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹ is phenyl optionally substituted withone or more R¹⁴ substituents. In some embodiments, A¹ is phenylsubstituted by at least one halogen substituent and optionally furthersubstituted with one or more R¹⁴ substituents. In some embodiments, A¹is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is 5-10 membered heteroaryl optionallysubstituted with one or more substituents. In some embodiments, A¹ is5-10 membered heteroaryl substituted by at least one halogen substituentand optionally further substituted with one or more R¹⁴ substituents. Insome embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹ is pyridyl optionally substituted withone or more R¹⁴ substituents. In some embodiments, A¹ is pyridylsubstituted by at least one halogen substituent and optionally furthersubstituted with one or more R¹⁴ substituents. In some embodiments, A¹is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (2-3), A² is C₆-C₁₀ arylsubstituted by at least one halogen substituent and optionally furthersubstituted with one or more R¹⁶ substituents, or 5-10 memberedheteroaryl substituted by at least one halogen substituent andoptionally further substituted with one or more R¹⁶ substituents.

In some embodiments of the compounds of formula (2-3), A² is C₆-C₁₀ aryloptionally substituted with one or more R¹⁶ substituents. In someembodiments, A² is C₆-C₁₀ aryl substituted by at least one halogensubstituent and optionally further substituted with one or more R¹⁶substituents. In some embodiments, A² is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A² is phenyl optionally substituted withone or more R¹⁶ substituents. In some embodiments, A² is phenylsubstituted by at least one halogen substituent and optionally furthersubstituted with one or more R¹⁶ substituents. In some embodiments, A²is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A² is 5-10 membered heteroaryl optionallysubstituted with one or more R¹⁶ substituents. In some embodiments, A²is 5-10 membered heteroaryl substituted by at least one halogensubstituent and optionally further substituted with one or more R¹⁶substituents. In some embodiments, A² is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A² is pyridyl optionally substituted withone or more R¹⁶ substituents. In some embodiments, A² is pyridylsubstituted by at least one halogen substituent and optionally furthersubstituted with one or more R¹⁶ substituents. In some embodiments, A²is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (2-3):

-   -   X¹ is N;    -   X² is CH;    -   Y¹ is a bond;    -   Y² is selected from the group consisting of NR^(Y2) and O;    -   R^(Y2) is hydrogen or C₁-C₆ alkyl;    -   q1 is 1; and    -   r and s are both 1.

In some embodiments of the compounds of formula (2-3):

-   -   X¹ is N;    -   X² is CH;    -   Y¹ is a bond;    -   Y² is NR^(Y2);    -   R^(Y2) is hydrogen;    -   q1 is 1; and    -   r and s are both 1.

In some embodiments of the compounds of formula (2-3), R^(9a) and R^(9b)are taken together to form an oxo (═O) substituent. In some embodimentsof the compounds of formula (2-3), R^(9a) and R^(9b) are taken togetherto form an imido (═NH) substituent. In some embodiments of the compoundsof formula (2-3), R^(9a) and R^(9b) are both hydrogen.

In some embodiments of the compounds of formula (2-3), R^(10a) ishydrogen and R^(10b) is hydrogen.

In some embodiments of the compounds of formula (2-3), R^(10a) is—OR^(10a-a) and R^(10b) is hydrogen. In some embodiments, R^(10a-a) isselected from the group consisting of hydrogen and C₁-C₆ alkyl. In someembodiments, R^(10a-a) is hydrogen. In some embodiments, R^(10a-a) isC₁-C₆ alkyl. In some embodiments, R^(10a-a) and R^(Y2) may be takentogether to form a carbonyl (C═O) moiety.

In some embodiments of the compounds of formula (2-3), R^(10a) is—NR^(10a-b)R^(10a-c) and R^(10b) is hydrogen. In some embodiments,R^(10a-b) and R^(10a-c), independently of each other, are selected fromthe group consisting of hydrogen and C₁-C₆ alkyl. In some embodiments,R^(10a-b) and R^(10a-c) are hydrogen. In some embodiments, R^(10a-b) andR^(10a-c) are C₁-C₆ alkyl.

In some embodiments of the compounds of formula (2-3), A¹ is C₆-C₁₀ arylsubstituted by at least one halogen substituent and optionally furthersubstituted with one or more R¹⁴ substituents, or 5-10 memberedheteroaryl substituted by at least one halogen substituent andoptionally further substituted with one or more R¹⁴ substituents.

In some embodiments of the compounds of formula (2-3), A¹ is C₆-C₁₀ aryloptionally substituted with one or more R¹⁴ substituents. In someembodiments, A¹ is C₆-C₁₀ aryl substituted by at least one halogensubstituent and optionally further substituted with one or more R¹⁴substituents. In some embodiments, A¹ is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹ is phenyl optionally substituted withone or more R¹⁴ substituents. In some embodiments, A¹ is phenylsubstituted by at least one halogen substituent and optionally furthersubstituted with one or more R¹⁴ substituents. In some embodiments, A¹is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is 5-10 membered heteroaryl optionallysubstituted with one or more R¹⁴ substituents. In some embodiments, A¹is 5-10 membered heteroaryl substituted by at least one halogensubstituent and optionally further substituted with one or more R¹⁴substituents. In some embodiments, A¹ is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹ is pyridyl optionally substituted withone or more R¹⁴ substituents. In some embodiments, A¹ is pyridylsubstituted by at least one halogen substituent and optionally furthersubstituted with one or more R¹⁴ substituents. In some embodiments, A¹is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (2-3), A² is C₆-C₁₀ arylsubstituted by at least one halogen substituent and optionally furthersubstituted with one or more R¹⁶ substituents, or 5-10 memberedheteroaryl substituted by at least one halogen substituent andoptionally further substituted with one or more R¹⁶ substituents.

In some embodiments of the compounds of formula (2-3), A² is C₆-C₁₀ aryloptionally substituted with one or more R¹⁶ substituents. In someembodiments, A² is C₆-C₁₀ aryl substituted by at least one halogensubstituent and optionally further substituted with one or more R¹⁶substituents. In some embodiments, A² is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A² is phenyl optionally substituted withone or more R¹⁶ substituents. In some embodiments, A² is phenylsubstituted by at least one halogen substituent and optionally furthersubstituted with one or more R¹⁶ substituents. In some embodiments, A²is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A² is 5-10 membered heteroaryl optionallysubstituted with one or more R¹⁶ substituents. In some embodiments, A²is 5-10 membered heteroaryl substituted by at least one halogensubstituent and optionally further substituted with one or more R¹⁶substituents. In some embodiments, A² is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A² is pyridyl optionally substituted withone or more R¹⁶ substituents. In some embodiments, A² is pyridylsubstituted by at least one halogen substituent and optionally furthersubstituted with one or more R¹⁶ substituents. In some embodiments, A²is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (2-3):

-   -   X¹ is CH;    -   X² is N;    -   Y¹ is selected from the group consisting of NR^(Y1) and O;    -   R^(Y1) is hydrogen or C₁-C₆ alkyl;    -   Y² is a bond;    -   q1 is 1;    -   r and s are both 1;    -   A¹ is C₆-C₁₀ aryl substituted by at least two halogen        substituents and optionally further substituted with one or more        R¹⁴ substituents, or 5-10 membered heteroaryl substituted by at        least two halogen substituents and optionally further        substituted with one or more R¹⁴ substituents; and    -   A² is C₆-C₁₀ aryl substituted by at least two halogen        substituents and optionally further substituted with one or more        R¹⁶ substituents, or 5-10 membered heteroaryl substituted by at        least two halogen substituents and optionally further        substituted with one or more R¹⁶ substituents.

In some embodiments of the compounds of formula (2-3):

-   -   X¹ is CH;    -   X² is N;    -   Y¹ is NR^(Y1);    -   R^(Y1) is hydrogen;    -   Y² is a bond;    -   q1 is 1;    -   r and s are both 1;    -   A¹ is C₆-C₁₀ aryl substituted by at least two halogen        substituents and optionally further substituted with one or more        R¹⁴ substituents, or 5-10 membered heteroaryl substituted by at        least two halogen substituents and optionally further        substituted with one or more R¹⁴ substituents; and    -   A² is C₆-C₁₀ aryl substituted by at least two halogen        substituents and optionally further substituted with one or more        R¹⁶ substituents, or 5-10 membered heteroaryl substituted by at        least two halogen substituents and optionally further        substituted with one or more R¹⁶ substituents.

In some embodiments of the compounds of formula (2-3), R^(9a) and R^(9b)are both hydrogen.

In some embodiments of the compounds of formula (2-3), R^(10a) ishydrogen and R^(10b) is hydrogen.

In some embodiments of the compounds of formula (2-3), R^(10a) is—OR^(10a-a) and R^(10b) is hydrogen. In some embodiments, R^(10a-a) isselected from the group consisting of hydrogen and C₁-C₆ alkyl. In someembodiments, R^(10a-a) is hydrogen. In some embodiments, R^(10a-a) isC₁-C₆ alkyl. In some embodiments, R^(10a-a) and R^(Y2) may be takentogether to form a carbonyl (C═O) moiety.

In some embodiments of the compounds of formula (2-3), R^(10a) is—NR^(10a-b)R^(10a-c) and R^(10b) is hydrogen. In some embodiments,R^(10a-b) and R^(10a-c), independently of each other, are selected fromthe group consisting of hydrogen and C₁-C₆ alkyl. In some embodiments,R^(10a-b) and R^(10a-c) are hydrogen. In some embodiments, R^(10a-b) andR^(10a-c) are C₁-C₆ alkyl.

In some embodiments of the compounds of formula (2-3), A¹ is C₆-C₁₀ arylsubstituted by at least two halogen substituents and optionally furthersubstituted with one or more R¹⁴ substituents, or 5-10 memberedheteroaryl substituted by at least two halogen substituents andoptionally further substituted with one or more R¹⁴ substituents.

In some embodiments of the compounds of formula (2-3), A¹ is C₆-C₁₀ arylsubstituted by at least two halogen substituents and optionally furthersubstituted with one or more R¹⁴ substituents. In some embodiments, A¹is phenyl substituted by at least two halogen substituents andoptionally further substituted with one or more R¹⁴ substituents. Insome embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹ is 5-10 membered heteroarylsubstituted by at least two halogen substituents and optionally furthersubstituted with one or more R¹⁴ substituents.

In some embodiments of the compounds of formula (2-3), A² is C₆-C₁₀ arylsubstituted by at least two halogen substituents and optionally furthersubstituted with one or more R¹⁶ substituents, or 5-10 memberedheteroaryl substituted by at least two halogen substituents andoptionally further substituted with one or more R¹⁶ substituents.

In some embodiments of the compounds of formula (2-3), A² is C₆-C₁₀ arylsubstituted by at least two halogen substituents and optionally furthersubstituted with one or more R¹⁶ substituents. In some embodiments, A²is phenyl substituted by at least two halogen substituents andoptionally further substituted with one or more R¹⁶ substituents. Insome embodiments, A² is

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A² is 5-10 membered heteroarylsubstituted by at least two halogen substituent and optionally furthersubstituted with one or more R¹⁶ substituents.

In some embodiments of the compounds of formula (2-3), A¹ is C₆-C₁₀ aryloptionally substituted with one or more R¹⁴ substituents. In someembodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹ is phenyl optionally substituted withone or more R¹⁴ substituents. In some embodiments, A¹ is selected fromthe group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (2-3), A¹ is 5-10membered heteroaryl optionally substituted with one or more R¹⁴substituents. In some embodiments, A¹ is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹ is pyridyl optionally substituted withone or more RH substituents. In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (2-3):

-   -   q¹ is 0;    -   A¹ is a substituent of formula (A¹-a)

-   -   R^(6a) is OR^(6a-a); and    -   R^(6b) is hydrogen.

In some embodiments of the compounds of formula (2-3):

-   -   R^(5a) and R^(5b) are taken together to form an oxo (═O)        substituent;    -   R^(6a) is hydrogen; and    -   R^(6b) is hydrogen.

In some embodiments of the compounds of formula (2-3), (A¹-a) isselected from the group consisting of:

In some embodiments of the compounds of formula (2-3), (A¹-a) is (A¹-b).

In some embodiments of the compounds of formula (2-3), (A¹-a) is (A¹-c).

In some embodiments of the compounds of formula (2-3), (A¹-a) is (A¹-d).

In some embodiments of the compounds of formula (2-3), (A¹-a) or (A¹-b)is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A¹-a) or (A¹-b) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A¹-a) or (A¹-b) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A¹-a) or (A¹-b) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (2-3), (A¹-a) or (A¹-c)is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A¹-a) or (A¹-c) is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (2-3):

-   -   R^(9a) and R^(9b) are taken together to form an oxo (═O)        substituent or an imido (═NH) substituent, or alternatively,        R^(9a) and R^(9b) are both hydrogen;    -   R^(10a) is selected from the group consisting of hydrogen,        —OR^(10a-a), and —NR^(10a-b)R^(10a-c);    -   R^(10b) is hydrogen; and    -   R^(12a) and R^(12b) are both hydrogen.

In some embodiments of the compounds of formula (2-3), R^(9a) and R^(9b)are taken together to form an oxo (═O) substituent. In some embodiments,R^(10a) is hydrogen. In some embodiments, R^(10a) is —OR^(10a-a). Insome embodiments, R^(10a) is NR^(10a-b)R^(10a-c).

In some embodiments of the compounds of formula (2-3), R^(9a) and R^(9b)are taken together to form an imido (═NH) substituent. In someembodiments, R^(10a) is hydrogen. In some embodiments, R^(10a) is—OR^(10a-a). In some embodiments, R^(10a) is NR^(10a-b)R^(10a-c).

In some embodiments of the compounds of formula (2-3), R^(9a) and R^(9b)are both hydrogen. In some embodiments, R^(10a) is hydrogen. In someembodiments, R^(10a) is —OR^(10a-a). In some embodiments, R^(10a) isNR^(10a-b)R^(10a-c) _(.)

In some embodiments of the compounds of formula (2-3):

-   -   X² is CH;    -   Y² is NR^(Y2);    -   R^(9a) and R^(9b) are both hydrogen;    -   R^(10a) is OR^(10a-a);    -   R^(12a) and R^(12b) are both hydrogen; and    -   R^(10a-a) and R^(Y2) are taken together to form a carbonyl (C═O)        moiety.

In some embodiments of the compounds of formula (2-3), A² is C₆-C₁₀ aryloptionally substituted with one or more R¹⁶ substituents. In someembodiments, A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A² is phenyl optionally substituted withone or more R¹⁶ substituents. In some embodiments, A² is selected fromthe group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (2-3), A² is 5-10membered heteroaryl optionally substituted with one or more R¹⁶substituents. In some embodiments, A² is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A² is pyridyl optionally substituted withone or more R¹⁶ substituents. In some embodiments, A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, the compound of formula (I) is a compound offormula (2-4):

or a pharmaceutically acceptable salt thereof;wherein:

-   -   A¹ is selected from the group consisting of:        -   a substituent of formula (A¹-a)

-   -   -   C₆-C₁₀ aryl optionally substituted with one or more R¹⁴            substituents; and        -   5-10 membered heteroaryl optionally substituted with one or            more R¹⁴ substituents;

    -   A² is C₆-C₁₀ aryl optionally substituted with one or more R¹⁶        substituents; or 5-10 membered heteroaryl optionally substituted        with one or more R¹⁶ substituents;

    -   R^(11a) and R^(11b) are both hydrogen;

    -   R^(12a) and R^(12b) are both hydrogen;

and wherein X¹, X², Y¹, R^(Y1), Y², R^(Y2), q¹, r, s, Z¹, R^(Z1-1),R^(Z1-2), Z², R^(Z2-1), R^(Z2-2), Z³, x1, R^(1a), R^(1b), R^(2a),R^(2b), R^(3a), R^(3b), R^(4a), R^(4b), R^(5a), R^(5b), R^(6a),R^(6a-a), R^(6a-b), R^(6a-c), R^(6b), R¹³, R¹⁴, and R¹⁶ are as definedin compounds of formula (I).

In some embodiments of the compounds of formula (2-4), X¹ is CH and X²is CH. In some embodiments, r is 1 and s is 1.

In some embodiments of the compounds of formula (2-4), X¹ is CH, X² is Nand Y² is a bond. In some embodiments, r is 1 and s is 1. In someembodiments, r is 0 and s is 2.

In some embodiments of the compounds of formula (2-4), X¹ is N, Y¹ is abond, and X² is CH. In some embodiments, r is 1 and s is 1. In someembodiments, r is 0 and s is 2.

In some embodiments of the compounds of formula (2-4), X¹ is N, Y¹ is abond, X² is N and Y² is a bond. In some embodiments, r is 1 and s is 1.In some embodiments, r is 0 and s is 2.

In some embodiments of the compounds of formula (2-4):

-   -   q¹ is 1;    -   A¹ is selected C₆-C₁₀ aryl optionally substituted with one or        more R¹⁴ substituents; or 5-10 membered heteroaryl optionally        substituted with one or more R¹⁴ substituents;    -   R^(5a) and R^(5b) are taken together to form an oxo (═O)        substituent or an imido (═NH) substituent, or alternatively,        R^(5a) and R^(5b) are both hydrogen;    -   R^(6a) is selected from the group consisting of hydrogen,        —OR^(6a-a), and —NR^(6a-b)R^(6a-c); and    -   R^(6b) is hydrogen;    -   or alternatively, R^(6a) and R^(6b) are taken together to form a        —CH₂—O—CH₂— moiety.

In some embodiments of the compounds of formula (2-4), R^(5a) and R^(5b)are both hydrogen; and R^(6a) and R^(6b) are taken together to form a—CH₂—O—CH₂— moiety.

In some embodiments of the compounds of formula (2-4), A¹ is C₆-C₁₀ aryloptionally substituted with one or more R¹⁴ substituents. In someembodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹ is phenyl optionally substituted withone or more R¹⁴ substituents. In some embodiments, A¹ is selected fromthe group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (2-4), A¹ is 5-10membered heteroaryl optionally substituted with one or more R¹⁴substituents. In some embodiments, A¹ is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹ is pyridyl optionally substituted withone or more R¹⁴ substituents. In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (2-4), A² is C₆-C₁₀ aryloptionally substituted with one or more R¹⁶ substituents. In someembodiments, A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A² is phenyl optionally substituted withone or more R¹⁶ substituents. In some embodiments, A² is selected fromthe group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (2-4), A² is 5-10membered heteroaryl optionally substituted with one or more R¹⁶substituents. In some embodiments, A² is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A² is pyridyl optionally substituted withone or more R¹⁶ substituents. In some embodiments, A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is wherein the * represents the attachment pointto the remainder of the molecule; and A² is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, the compound of formula (I) is a compound offormula (3-3):

or a pharmaceutically acceptable salt thereof;wherein:

-   -   A¹ is C₆-C₁₀ aryl optionally substituted with one or more RH        substituents; or 5-10 membered heteroaryl optionally substituted        with one or more R¹⁴ substituents;    -   A² is C₆-C₁₀ aryl optionally substituted with one or more R¹⁶        substituents; or 5-10 membered heteroaryl optionally substituted        with one or more R¹⁶ substituents;

and wherein X¹, X², Y¹, R^(Y1), Y², R^(Y2), r, s, R^(1a), R^(1b),R^(2a), R^(2b), R^(3a), R^(3b), R^(4a), R^(4b), R^(5a), R^(5b), R^(6a),R^(6a-a), R^(6a-b), R^(6a-c), R^(6b), R^(8a), R^(8b), R^(9a), R^(9b),R^(10a), R^(10a-a), R^(10a-b), R^(10a-c), R^(10b), R^(12a), R^(12b),R¹⁴, and R¹⁶ are as defined in compounds of formula (I).

In some embodiments of the compounds of formula (3-3), X¹ is CH and X²is CH. In some embodiments, r is 1 and s is 1.

In some embodiments of the compounds of formula (3-3), X¹ is CH, X² is Nand Y² is a bond. In some embodiments, r is 1 and s is 1. In someembodiments, r is 0 and s is 2.

In some embodiments of the compounds of formula (3-3), X¹ is N, Y¹ is abond, and X² is CH. In some embodiments, r is 1 and s is 1. In someembodiments, r is 0 and s is 2.

In some embodiments of the compounds of formula (3-3), X¹ is N, Y¹ is abond, X² is N and Y² is a bond. In some embodiments, r is 1 and s is 1.In some embodiments, r is 0 and s is 2.

In some embodiments of the compounds of formula (3-3):

-   -   R^(5a) and R^(5b) are taken together to form an oxo (═O)        substituent or an imido (═NH) substituent, or alternatively,        R^(5a) and R^(5b) are both hydrogen;    -   R^(6a) is selected from the group consisting of hydrogen,        —OR^(6a-a), and —NR^(6a-b)R^(6a-c);    -   R^(10b) is hydrogen; and    -   R^(12a) and R^(12b) are both hydrogen.

In some embodiments of the compounds of formula (3-3), R^(9a) and R^(9b)are taken together to form an oxo (═O) substituent. In some embodiments,R^(10a) is hydrogen. In some embodiments, R^(10a) is OR^(10a-a). In someembodiments, R^(10a) is NR^(10a-b)R^(10a-c) _(.)

In some embodiments of the compounds of formula (3-3), R^(9a) and R^(9b)are taken together to form an imido (═NH) substituent. In someembodiments, R^(10a) is hydrogen. In some embodiments, R^(10a) is—OR^(10a-a). In some embodiments, R^(10a) is NR^(10a-b)R^(10a-c).

In some embodiments of the compounds of formula (3-3), R^(9a) and R^(9b)are both hydrogen. In some embodiments, R^(10a) is hydrogen. In someembodiments, R^(10a) is —OR^(10a-a). In some embodiments, R^(10a) isNR^(10a-b)R^(10a-c) _(.)

In some embodiments of the compounds of formula (3-3), A¹ is C₆-C₁₀ aryloptionally substituted with one or more R¹⁴ substituents. In someembodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹ is phenyl optionally substituted withone or more R¹⁴ substituents. In some embodiments, A¹ is selected fromthe group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (3-3), A¹ is 5-10membered heteroaryl optionally substituted with one or more R¹⁴substituents. In some embodiments, A¹ is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹ is pyridyl optionally substituted withone or more R¹⁴ substituents. In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (3-3):

-   -   X² is CH;    -   Y² is NR^(Y2);    -   R^(9a) and R^(9b) are both hydrogen;    -   R^(10a) is —OR^(10a-a);    -   R^(12a) and R^(12b) are both hydrogen; and    -   R^(10a-a) and R^(Y2) are taken together to form a carbonyl (C═O)        moiety.

In some embodiments of the compounds of formula (3-3), A² is C₆-C₁₀ aryloptionally substituted with one or more R¹⁶ substituents. In someembodiments, A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A² is phenyl optionally substituted withone or more R¹⁶ substituents. In some embodiments, A² is selected fromthe group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (3-3), A² is 5-10membered heteroaryl optionally substituted with one or more R¹⁶substituents. In some embodiments, A² is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A² is pyridyl optionally substituted withone or more R¹⁶ substituents. In some embodiments, A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is wherein the * represents the attachment pointto the remainder of the molecule; and A² is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, the compound of formula (I) is a compound offormula (3-4):

or a pharmaceutically acceptable salt thereof;wherein:

-   -   A¹ is C₆—C to aryl optionally substituted with one or more R¹⁴        substituents; or 5-10 membered heteroaryl optionally substituted        with one or more R¹⁴ substituents;    -   A² is C₆-C₁₀ aryl optionally substituted with one or more R¹⁶        substituents; or 5-10 membered heteroaryl optionally substituted        with one or more R¹⁶ substituents;    -   R^(11a) and R^(11b) are both hydrogen;    -   R^(12a) and R^(12b) are both hydrogen;

and wherein X¹, X², Y¹, R^(Y1), R^(Y2), r, s, R^(1a), R^(1b), R^(2a),R^(2b), R^(3a), R^(3b), R^(4a), R^(4b), R^(5a), R^(5b), R^(6a),R^(6a-a), R^(6a-b), R^(6a-c), R^(6b), R^(8a), R^(8b), R¹⁴, and R¹⁶ areas defined in compounds of formula (I).

In some embodiments of the compounds of formula (3-4), X¹ is CH and X²is CH. In some embodiments, r is 1 and s is 1.

In some embodiments of the compounds of formula (3-4), X¹ is CH, X² is Nand Y² is a bond. In some embodiments, r is 1 and s is 1. In someembodiments, r is 0 and s is 2.

In some embodiments of the compounds of formula (3-4), X¹ is N, Y¹ is abond, and X² is CH. In some embodiments, r is 1 and s is 1. In someembodiments, r is 0 and s is 2.

In some embodiments of the compounds of formula (3-4), X¹ is N, Y¹ is abond, X² is N and Y² is a bond. In some embodiments, r is 1 and s is 1.In some embodiments, r is 0 and s is 2.

In some embodiments of the compounds of formula (3-4):

-   -   R^(5a) and R^(5b) are taken together to form an oxo (═O)        substituent or an imido (═NH) substituent, or alternatively,        R^(5a) and R^(5b) are both hydrogen;    -   R^(6a) is selected from the group consisting of hydrogen,        —OR^(6a-a), and NR^(6a-b)R^(6a-c);    -   R^(10b) is hydrogen; and    -   R^(12a) and R^(12b) are both hydrogen.

In some embodiments of the compounds of formula (3-4), R^(9a) and R^(9b)are taken together to form an oxo (═O) substituent. In some embodiments,R^(10a) is hydrogen. In some embodiments, R^(10a) is —OR^(10a-a). Insome embodiments, R^(10a) is NR^(10a-b)R^(10a-c).

In some embodiments of the compounds of formula (3-4), R^(9a) and R^(9b)are taken together to form an imido (═NH) substituent. In someembodiments, R^(10a) is hydrogen. In some embodiments, R^(10a) is—OR^(10a-a). In some embodiments, R^(10a) is NR^(10a-b)R^(10a-c).

In some embodiments of the compounds of formula (3-4), R^(9a) and R^(9b)are both hydrogen. In some embodiments, R^(10a) is hydrogen. In someembodiments, R^(10a) is OR^(10a-a). In some embodiments, R^(10a) isNR^(10a-b)R^(10a-c) _(.)

In some embodiments of the compounds of formula (3-4):

-   -   X¹ is CH;    -   Y¹ is NR^(Y1);    -   R^(5a) and R^(5b) are both hydrogen;    -   R^(6a) is —OR^(6a-a);    -   R^(8a) and R^(8b) are both hydrogen; and    -   R^(6a-a) and R^(Y1) are taken together to form a carbonyl (C═O)        moiety.

In some embodiments of the compounds of formula (3-4), A¹ is C₆-C₁₀ aryloptionally substituted with one or more R¹⁴ substituents. In someembodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹ is phenyl optionally substituted withone or more R¹⁴ substituents. In some embodiments, A¹ is selected fromthe group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (3-4), A¹ is 5-10membered heteroaryl optionally substituted with one or more R¹⁴substituents. In some embodiments, A¹ is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹ is pyridyl optionally substituted withone or more RH substituents. In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (3-4), A² is C₆-C₁₀ aryloptionally substituted with one or more R¹⁶ substituents. In someembodiments, A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A² is phenyl optionally substituted withone or more R¹⁶ substituents. In some embodiments, A² is selected fromthe group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (3-4), A² is 5-10membered heteroaryl optionally substituted with one or more R¹⁶substituents. In some embodiments, A² is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A² is pyridyl optionally substituted withone or more R¹⁶ substituents. In some embodiments, A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A′-a) or (A′-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, the compound of formula (I) is a compound offormula (4-4):

or a pharmaceutically acceptable salt thereof;wherein:

-   -   A¹ is C₆-C₁₀ aryl optionally substituted with one or more R¹⁴        substituents; or 5-10 membered heteroaryl optionally substituted        with one or more R¹⁴ substituents;    -   A² is C₆-C₁₀ aryl optionally substituted with one or more R¹⁶        substituents; or 5-10 membered heteroaryl optionally substituted        with one or more R¹⁶ substituents;    -   R^(7a) and R^(7b) are both hydrogen;    -   R^(8a) and R^(8b) are both hydrogen;    -   R^(11a) and R^(11b) are both hydrogen;    -   R^(12a) and R^(12b) are both hydrogen;

and wherein X¹, X², Y¹, R^(Y1), R^(Y2), r, s, R^(1a), R^(1b), R^(2a),R^(2b), R^(3a), R^(3b), R^(4a), R^(4b), R¹⁴, and R¹⁶ are as defined incompounds of formula (I).

In some embodiments of the compounds of formula (4-4), X¹ is CH and X²is CH. In some embodiments, r is 1 and s is 1.

In some embodiments of the compounds of formula (4-4), X¹ is CH, X² is Nand Y² is a bond. In some embodiments, r is 1 and s is 1. In someembodiments, r is 0 and s is 2.

In some embodiments of the compounds of formula (4-4), X¹ is N, Y¹ is abond, and X² is CH. In some embodiments, r is 1 and s is 1. In someembodiments, r is 0 and s is 2.

In some embodiments of the compounds of formula (4-4), X¹ is N, Y¹ is abond, X² is N and Y² is a bond. In some embodiments, r is 1 and s is 1.In some embodiments, r is 0 and s is 2.

In some embodiments of the compounds of formula (4-4), A¹ is C₆-C₁₀ aryloptionally substituted with one or more R¹⁴ substituents. In someembodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹ is phenyl optionally substituted withone or more R¹⁴ substituents. In some embodiments, A¹ is selected fromthe group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (4-4), A¹ is 5-10membered heteroaryl optionally substituted with one or more R¹⁴substituents. In some embodiments, A¹ is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹ is pyridyl optionally substituted withone or more R¹⁴ substituents. In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (4-4), A² is C₆-C₁₀ aryloptionally substituted with one or more R¹⁶ substituents. In someembodiments, A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A² is phenyl optionally substituted withone or more R¹⁶ substituents. In some embodiments, A² is selected fromthe group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (4-4), A² is 5-10membered heteroaryl optionally substituted with one or more R¹⁶substituents. In some embodiments, A² is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A² is pyridyl optionally substituted withone or more R¹⁶ substituents. In some embodiments, A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, (A¹-a) or (A¹-c) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and (A²-a) or (A²-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and A² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments, A¹ is

wherein the * represents the attachment point to the remainder of themolecule; and A² is

wherein the * represents the attachment point to the remainder of themolecule.

In one aspect, provided is a compound of formula (II):

or a pharmaceutically acceptable salt thereof;wherein:

-   -   m3 is 0 or 1;    -   n3 is 0 or 1;    -   r2 is 0, 1, or 2;    -   s2 is 0, 1, or 2;    -   X³ is CH or N;    -   X⁴ is CH or N;    -   provided that at least one of X³ and X⁴ is CH;    -   Y³ is selected from the group consisting of a bond, NR^(Y3), and        0;        -   wherein R^(Y3) is hydrogen or C₁-C₆ alkyl;    -   Y⁴ is selected from the group consisting of a bond, NR^(Y4), and        0;        -   wherein R^(Y4) is hydrogen or C₁-C₆ alkyl;    -   provided that:        -   when X³ is N, then Y³ is a bond and m3 is 1;        -   when X⁴ is N, then Y⁴ is a bond and n3 is 1;    -   A³ is selected from the group consisting of:        -   a substituent of the formula (A³-a)

-   -   -   wherein            -   * represents the attachment point to the remainder of                the molecule;            -   Z⁷ is selected from the group consisting of                CR^(Z7-1)R^(Z7-2), NR^(Z7-2), O, S, and                —CR^(Z7-1)═CR^(Z7-1)—;                -   wherein                -   R^(Z7-1) is H or R²⁷; and                -   R^(Z7-2) is H or R²⁷;            -   Z⁸ is selected from the group consisting of                CR^(ZB-1)R^(Z8-2), NR^(Z8-2); O, S, and                —CR^(Z8-1)═CR^(Z8-1)—;                -   wherein                -   R^(Z8-1) is H or R²⁷; and                -   R^(Z8-2) is H or R²⁷;            -   Z⁹, independently at each occurrence, is C or N,                provided that at least one Z⁹ is C;            -   R²⁶ is hydrogen or R²⁷, or R²⁶ and R^(Z7-2) are taken                together to form a double bond between the carbon atom                bearing R²⁶ and Z⁷; and            -   x3 is 0, 1, 2, 3, or 4, provided than when one Z⁹ is N,                then x3 is not 4;        -   C₆-C₁₀ aryl optionally substituted with one or more R²⁷            substituent; and 5-10 membered heteroaryl optionally            substituted with one or more R²⁷ substituent;            -   R²⁷ is selected, independently at each occurrence, from                the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆                haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl),                —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,                —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆                alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(27-a)R^(27-b), —CN,                —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),                —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆                haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆                haloalkyl)₂, —C(O)NR^(27-a)R^(27-b), —S(O)₂OH,                —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),                —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆                haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆                haloalkyl)₂, —S(O)₂NR^(27-a)R^(27-b), —OC(O)H,                —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(27-a) and R^(27-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;

    -   A⁴ is selected from the group consisting of:        -   a substituent of the formula (A⁴-a)

-   -   -   wherein            -   * represents the attachment point to the remainder of                the molecule; Z¹⁰ is selected from the group consisting                of CR^(Z10-1)R^(Z10-2), NR^(Z10-2), O, S, and                —CR^(Z10-1)═CR^(Z10-1)—;                -   wherein                -   R^(Z10-1) is H or R²⁹; and                -   R^(Z10-2) is H or R²⁹;            -   Z¹¹ is selected from the group consisting of                CR^(Z11-1)R^(Z11-2), NR^(Z11-2); O, S, and                —CR^(Z11-1)═CR^(Z11-1)—;                -   wherein                -   R^(Z11-1) is H or R²⁹; and                -   R^(Z11-2) is H or R²⁹;            -   Z¹², independently at each occurrence, is C or N,                provided that at least one Z¹² is C;            -   R²⁸ is hydrogen or R²⁹, or R²⁸ and R^(Z10-2) are taken                together to form a double bond between the carbon atom                bearing R²⁸ and Z¹⁰, and            -   x4 is 0, 1, 2, 3, or 4, provided than when one Z¹² is N,                then x4 is not 4;        -   C₆-C₁₀ aryl optionally substituted with one or more R²⁹            substituent; and        -   5-10 membered heteroaryl optionally substituted with one or            more R²⁹ substituent;            -   R²⁹ is selected, independently at each occurrence, from                the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆                haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl),                —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,                —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆                alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(29-a)R^(29-b), —CN,                —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),                —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆                haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆                haloalkyl)₂, —C(O)NR^(29-a)R^(29-b), —S(O)₂OH,                —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),                —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆                haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆                haloalkyl)₂, —S(O)₂NR^(29-a)R^(29-b), —OC(O)H,                —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(29-a) and R^(29-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;

    -   R^(17a) and R^(17b) are independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, and halogen;

    -   R^(18a) and R^(18b) are independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, and halogen;

    -   when present, R^(19a) and R^(19b) are independently at each        occurrence selected from the group consisting of hydrogen, C₁-C₆        alkyl, and halogen;

    -   when present, R^(20a) and R^(20b) are independently at each        occurrence selected from the group consisting of hydrogen, C₁-C₆        alkyl, and halogen;

    -   or alternatively, R^(17a) and R^(18a) are taken together to form        a C₁-C₆ alkylene moiety;

    -   or alternatively, R^(17a) and an R^(19a) moiety, when present,        are taken together to form a C₁-C₆ alkylene moiety, and R^(17b)        and the R^(19b) in the geminal position to the R^(19a) taken        together with R^(17a), are both hydrogen;

    -   or alternatively, an R^(19a) moiety, when present, and an        R^(20a) moiety, when present, are taken together to form a C₁-C₆        alkylene moiety, and the R^(19b) in the geminal position to the        R^(19a) taken together with the R^(20a) moiety and the R^(20b)        in the geminal position to the R^(20a) taken together with the        R^(19a) moiety, are both hydrogen;

    -   R^(21a) and R^(21b) are taken together to form an oxo (═O)        substituent or an imido (═NH) substituent, or alternatively,        R^(21a) and R^(21b) are both hydrogen;

    -   when present, R^(22a) and R^(22b) are both hydrogen;

    -   R^(23a) and R^(23b) are taken together to form an oxo (═O)        substituent or an imido (═NH) substituent, or alternatively,        R^(23a) and R^(23b) are both hydrogen;

    -   when present, R^(24a) is selected from the group consisting of        hydrogen, —OH, and —NH₂;

    -   or alternatively, R^(24a) and R^(Y4) are taken together to form        a #—C(═O)—O— group, wherein # represent the attachment point to        the nitrogen atom bearing R^(Y4);

    -   when present, R^(24b) is hydrogen; and when present, R^(25a) and        R^(25b) are both hydrogen;

    -   or alternatively, R^(25a), when present, and one R²⁹ of A⁴ are        taken together with the atoms connecting them to form a 5-6        membered heterocycloalkenyl optionally substituted with one or        more R²⁹ substituent, and R^(25b) is H;

    -   or alternatively, R^(25a), when present, R^(25b), when present,        and one R²⁹ of A⁴ are taken together with the atoms connecting        them to form a 5-6 membered heteroaryl optionally substituted        with one or more R²⁹ substituent;

    -   and further provided that one of (i), (ii), (iii) and (iv)        applies:

    -   (i) when m3 is 0 and n3 is 0, then:        -   X³ is CH and Y³ is NR^(Y3);        -   X⁴ is CH and Y⁴ is NR^(Y4);        -   R^(21a) and R^(21b) are taken together to form an oxo (═O)            substituent;        -   R^(23a) and R^(23b) are taken together to form an oxo (═O)            substituent;        -   A³ is a substituent of the formula (A³-a)

-   -   -   wherein            -   * represents the attachment point to the remainder of                the molecule;            -   Z⁷ is selected from the group consisting of                CR^(Z7-1)R^(Z7-2), NR^(Z7-2), O, S, and                —CR^(Z7-1)═CR^(Z7-1)—,                -   wherein                -   R^(Z7-1) is H or R²⁷; and                -   R^(Z7-2) is H or R²⁷;            -   Z⁸ is selected from the group consisting of                CR^(Z8-1)R^(Z8-2), NR^(Z8-2); 0, S, and                CR^(Z8-1)═CR^(Z8-1)—;                -   wherein                -   R^(Z8-1) is H or R²⁷; and                -   R^(Z8-2) is H or R²⁷;            -   Z⁹, independently at each occurrence, is C or N,                provided that at least one Z⁹ is C;            -   R²⁶ is hydrogen or R²⁷, or R²⁶ and R^(Z7-2) are taken                together to form a double bond between the carbon atom                bearing R²⁶ and Z⁷; R²⁷ is selected, independently at                each occurrence, from the group consisting of halogen,                C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OH, —O(C₁-C₆ alkyl),                —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆                haloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —NH(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂,                —NR^(27-a)R^(27-b), —CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl),                —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),                —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂,                —C(O)N(C₁-C₆ haloalkyl)₂, —C(O)NR^(27-a)R^(27-b),                —S(O)₂OH, —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆                haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl),                —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,                —S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(27-a)R^(27-b),                —OC(O)H, —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(27-a) and R^(27-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;            -   x3 is 0, 1, 2, 3, or 4, provided than when one Z⁹ is N,                then x3 is not 4;        -   A⁴ is a substituent of the formula (A⁴-a)

-   -   -   wherein            -   * represents the attachment point to the remainder of                the molecule;            -   Z¹⁰ is selected from the group consisting of                CR^(Z10-1)R^(Z10-2), NR^(Z10-2), O, S, and                —CR^(Z10-1)═CR^(Z10-1)—,                -   wherein                -   R^(Z10-1) is H or R²⁹; and                -   R^(Z10-2) is H or R²⁹;            -   Z¹¹ is selected from the group consisting of                CR^(Z11-1)R^(Z11-2), NR^(Z11-2), O, S, and                —CR^(Z11-1)═CR^(Z11-1)—,                -   wherein                -   R^(Z11-1) is H or R²⁹; and                -   R^(Z11-2) is H or R²⁹;            -   Z¹², independently at each occurrence, is C or N,                provided that at least one Z¹² is C;            -   R²⁸ is hydrogen or R²⁹, or R²⁸ and R^(Z10-2) are taken                together to form a double bond between the carbon atom                bearing R²⁸ and Z¹⁰;            -   R²⁹ is selected, independently at each occurrence, from                the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆                haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl),                —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,                —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆                alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(29-a)R^(29-b), —CN,                —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),                —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆                haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆                haloalkyl)₂, —C(O)NR^(29-a)R^(29-b), —S(O)₂OH,                —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),                —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆                haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆                haloalkyl)₂, —S(O)₂NR^(29-a)R^(29-b), —OC(O)H,                —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(29-a) and R^(29-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;            -   x4 is 0, 1, 2, 3, or 4, provided than when one Z¹² is N,                then x4 is not 4; and        -   provided that A³ and A⁴ are not both simultaneously a moiety            selected from group consisting of:

wherein the * represents the attachment point to the remainder of themolecule;

-   -   (ii) when m3 is 0 and n3 is 1, then:        -   r2 is 1 or 2;        -   s2 is 1 or 2;        -   X³ is CH and Y³ is NR^(Y3);        -   R^(21a) and R^(21b) are taken together to form an oxo (═O)            substituent;        -   R^(24a) is selected from the group consisting of hydrogen,            —OH, and —NH₂;        -   A³ is a substituent of the formula (A³-a)

-   -   -   wherein            -   * represents the attachment point to the remainder of                the molecule;            -   Z⁷ is selected from the group consisting of                CR^(Z7-1)R^(Z7-2), NR^(Z7-2), O, S, and                —CR^(Z7-1)═CR^(Z7-1)—;                -   wherein                -   R^(Z7-1) is H or R²⁷; and                -   R^(Z7-2) is H or R²⁷;            -   Z⁸ is selected from the group consisting of                CR^(Z8-1)R^(Z8-2), O, S, and —CR^(Z8-1)═CR^(Z8-1)—;                -   wherein                -   R^(Z8-1) is H or R²⁷; and                -   R^(Z8-2) is H or R²⁷;            -   Z⁹, independently at each occurrence, is C or N,                provided that at least one Z⁹ is C;            -   R²⁶ is hydrogen or R²⁷, or R²⁶ and R^(Z7-2) are taken                together to form a double bond between the carbon atom                bearing R²⁶ and Z⁷; R²⁷ is selected, independently at                each occurrence, from the group consisting of halogen,                C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OH, —O(C₁-C₆ alkyl),                —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆                haloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —NH(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂,                —NR^(27-a)R^(27-b), —CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl),                —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),                —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂,                —C(O)N(C₁-C₆ haloalkyl)₂, —C(O)NR^(27-a)R^(27-b),                —S(O)₂OH, —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆                haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl),                —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,                —S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(27-a)R^(27-b),                —OC(O)H, —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(27-a) and R^(27-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;            -   x3 is 0, 1, 2, 3, or 4, provided than when one Z⁹ is N,                then x3 is not 4;        -   A⁴ is C₆-C₁₀ aryl optionally substituted with one or more            R²⁹ substituent, or 5-10 membered heteroaryl optionally            substituted with one or more R²⁹ substituent;            -   R²⁹ is selected, independently at each occurrence, from                the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆                haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl),                —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,                —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆                alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(29-a)R^(29-b), —CN,                —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),                —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆                haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆                haloalkyl)₂, —C(O)NR^(29-a)R^(29-b), —S(O)₂OH,                —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),                —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆                haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆                haloalkyl)₂, —S(O)₂NR^(29-a)R^(29-b), —OC(O)H,                —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(29-a) and R^(29-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;        -   provided that when R^(23a) and R^(23b) are taken together to            form an oxo (═O) substituent, then R^(24a) is —OH or —NH₂;

    -   (iii) when m3 is 1 and n3 is 0, then:        -   X⁴ is CH and Y⁴ is NR^(Y4);        -   R^(21a) and R^(21b) are taken together to form an oxo (═O)            substituent or an imido (═NH) substituent;        -   R^(23a) and R^(23b) are taken together to form an oxo (═O)            substituent;        -   A³ is C₆-C₁₀ aryl optionally substituted with one or more            R²⁷ substituent, or 5-10 membered heteroaryl optionally            substituted with one or more R²⁷ substituent;            -   R²⁷ is selected, independently at each occurrence, from                the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆                haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl),                —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,                —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆                alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(27-a)R^(27-b), —CN,                —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),                —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆                haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆                haloalkyl)₂, —C(O)NR^(27-a)R^(27-b), —S(O)₂OH,                —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),                —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆                haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆                haloalkyl)₂, —S(O)₂NR^(27-a)R^(27-b), —OC(O)H,                —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(27-a) and R^(27-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;        -   A⁴ is a substituent of the formula (A⁴-a)

-   -   -   wherein            -   * represents the attachment point to the remainder of                the molecule;            -   Z¹⁰ is selected from the group consisting of                CR^(Z10-1)R^(Z10-2), NR^(Z10-2), O, S, and                —CR^(Z10-1)═CR^(Z10-1)—;                -   wherein                -   R^(Z10-1) is H or R²⁹; and                -   R^(Z10-2) is H or R²⁹;            -   Z¹¹ is selected from the group consisting of                CR^(Z11-1)R^(Z11-2), NR^(Z11-2), O, S, and                —CR^(Z11-1)═CR^(Z11-1)—;                -   wherein                -   R^(Z11-1) is H or R²⁹; and                -   R^(Z11-2) is H or R²⁹;            -   Z¹², independently at each occurrence, is C or N,                provided that at least one Z¹² is C;            -   R²⁸ is hydrogen or R²⁹, or R²⁸ and R^(Z10-2) are taken                together to form a double bond between the carbon atom                bearing R²⁸ and Z¹⁰; R²⁹ is selected, independently at                each occurrence, from the group consisting of halogen,                C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OH, —O(C₁-C₆ alkyl),                —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆                haloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —NH(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂,                —NR^(29-a)R^(29-b), —CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl),                —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),                —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂,                —C(O)N(C₁-C₆ haloalkyl)₂, —C(O)NR^(29-a)R^(29-b),                —S(O)₂OH, —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆                haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl),                —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,                —S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(29-a)R^(29-b),                —OC(O)H, —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(29-a) and R^(29-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;            -   x4 is 0, 1, 2, 3, or 4, provided than when one Z¹² is N,                then x4 is not 4;

    -   (iv) when m3 is 1 and n3 is 1, then:        -   R^(21a) and R^(21b) are taken together to form an oxo (═O)            substituent or an imido (═NH) substituent;        -   A³ is C₆-C₁₀ aryl optionally substituted with one or more            R²⁷ substituent, or 5-10 membered heteroaryl optionally            substituted with one or more R²⁷ substituent;            -   R²⁷ is selected, independently at each occurrence, from                the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆                haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl),                —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,                —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆                alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(27-a)R^(27-b), —CN,                —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),                —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆                haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆                haloalkyl)₂, —C(O)NR^(27-a)R^(27-b), —S(O)₂OH,                —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),                —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆                haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆                haloalkyl)₂, —S(O)₂NR^(27-a)R^(27-b), —OC(O)H,                —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(27-a) and R^(27-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;        -   A⁴ is C₆-C₁₀ aryl optionally substituted with one or more            R²⁹ substituent, or 5-10 membered heteroaryl optionally            substituted with one or more R²⁹ substituent;            -   R²⁹ is selected, independently at each occurrence, from                the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆                haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl),                —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,                —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆                alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(29-a)R^(29-b), —CN,                —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),                —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆                haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆                haloalkyl)₂, —C(O)NR^(29-a)R^(29-b), —S(O)₂OH,                —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),                —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆                haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆                haloalkyl)₂, —S(O)₂NR^(29-a)R^(29-b), —OC(O)H,                —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(29-a) and R^(29-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;        -   provided that:            -   when one of X³ or X⁴ is N, then r2 is 1 or 2 and s2 is 1                or 2; and            -   when R^(23a) and R^(23b) are taken together to form an                oxo (═O) substituent, then R^(24a) is —OH or —NH₂.

In some embodiments of compounds of formula (II):

-   -   m3 is 0 or 1;    -   n3 is 0 or 1;    -   r2 is 0, 1, or 2;    -   s2 is 0, 1, or 2;    -   X³ is CH or N;    -   X⁴ is CH or N;    -   provided that at least one of X³ and X⁴ is CH;    -   Y³ is selected from the group consisting of a bond, NR^(Y3), and        O;        -   wherein R^(Y3) is hydrogen or C₁-C₆ alkyl;    -   Y⁴ is selected from the group consisting of a bond, NR^(Y4), and        O;        -   wherein R^(Y4) is hydrogen or C₁-C₆ alkyl;    -   provided that:        -   when X³ is N, then Y³ is a bond and m3 is 1;        -   when X⁴ is N, then Y⁴ is a bond and n3 is 1;    -   A³ is selected from the group consisting of:

-   -   -   wherein            -   * represents the attachment point to the remainder of                the molecule;            -   Z⁷ is selected from the group consisting of                CR^(Z7-1)R^(Z7-2), NR^(Z7-2), O, S, and                —CR^(Z7-1)═CR^(Z7-1)—,                -   wherein                -   R^(Z7-1) is H or R²⁷; and                -   R^(Z7-2) is H or R²⁷;            -   Z⁸ is selected from the group consisting of                CR^(Z8-1)R^(Z8-2), NR^(Z8-2); O, S, and                —CR^(Z8-1)═CR^(Z8-1)—,                -   wherein                -   R^(Z8-1) is H or R²⁷; and                -   R^(Z8-2) is H or R²⁷;            -   R²⁶ is hydrogen or R²⁷, or R²⁶ and R^(Z7-2) are taken                together to form a double bond between the carbon atom                bearing R²⁶ and Z⁷; and            -   x3 is 0, 1, 2, 3, or 4;        -   C₆-C₁₀ aryl optionally substituted with one or more R²⁷            substituent; and 5-10 membered heteroaryl optionally            substituted with one or more R²⁷ substituent;            -   R²⁷ is selected, independently at each occurrence, from                the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆                haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl),                —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,                —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆                alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(27-a)R^(27-b), —CN,                —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),                —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆                haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆                haloalkyl)₂, —C(O)NR^(27-a)R^(27-b), —S(O)₂OH,                —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),                —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆                haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆                haloalkyl)₂, —S(O)₂NR^(27-a)R^(27-b), —OC(O)H,                —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(27-a) and R^(27-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;

    -   A⁴ is selected from the group consisting of:        -   a substituent of the formula (A⁴-b)

-   -   -   wherein            -   * represents the attachment point to the remainder of                the molecule;            -   Z¹⁰ is selected from the group consisting of                CR^(Z10-1)R^(Z10-2), NR^(Z10-2), O, S, and                —CR^(Z10-1)═CR^(Z10-1)—,                -   wherein                -   R^(Z10-1) is H or R²⁹; and                -   R^(Z10-2) is H or R²⁹;            -   Z¹¹ is selected from the group consisting of                CR^(Z11-1)R^(Z11-2), NR^(Z11-2), O, S, and                —CR^(Z11-1)═CR^(Z11-1)—,                -   wherein                -   R^(Z11-1) is H or R²⁹; and                -   R^(Z11-2) is H or R²⁹;            -   R²⁸ is hydrogen or R²⁹, or R²⁸ and R^(Z10-2) are taken                together to form a double bond between the carbon atom                bearing R²⁸ and Z¹⁰, and            -   x4 is 0, 1, 2, 3, or 4;        -   C₆-C₁₀ aryl optionally substituted with one or more R²⁹            substituent; and        -   5-10 membered heteroaryl optionally substituted with one or            more R²⁹ substituent;            -   R²⁹ is selected, independently at each occurrence, from                the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆                haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl),                —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,                —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆                alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(29-a)R^(29-b), —CN,                —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),                —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆                haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆                haloalkyl)₂, —C(O)NR^(29-a)R^(29-b), —S(O)₂OH,                —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),                —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆                haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆                haloalkyl)₂, —S(O)₂NR^(29-a)R^(29-b), —OC(O)H,                —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(29-a) and R^(29-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;

    -   R^(17a) and R^(17b) are independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, and halogen;

    -   R^(18a) and R^(18b) are independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, and halogen;

    -   when present, R^(19a) and R^(19b) are independently at each        occurrence selected from the group consisting of hydrogen, C₁-C₆        alkyl, and halogen;

    -   when present, R^(20a) and R^(20b) are independently at each        occurrence selected from the group consisting of hydrogen, C₁-C₆        alkyl, and halogen;

    -   or alternatively, R^(17a) and R^(18a) are taken together to form        a C₁-C₆ alkylene moiety;

    -   or alternatively, R^(17a) and an R^(19a) moiety, when present,        are taken together to form a C₁-C₆ alkylene moiety, and R^(17b)        and the R^(19b) in the geminal position to the R^(19a) taken        together with R^(17a), are both hydrogen;

    -   or alternatively, an R^(19a) moiety, when present, and an        R^(20a) moiety, when present, are taken together to form a C₁-C₆        alkylene moiety, and the R^(19b) in the geminal position to the        R^(19a) taken together with the R^(20a) moiety and the R^(20b)        in the geminal position to the R^(20a) taken together with the        R^(19a) moiety, are both hydrogen;

    -   R^(21a) and R^(21b) are taken together to form an oxo (═O)        substituent or an imido (═NH) substituent, or alternatively,        R^(21a) and R^(21b) are both hydrogen;

    -   when present, R^(22a) and R^(22b) are both hydrogen;

    -   R^(23a) and R^(23b) are taken together to form an oxo (═O)        substituent or an imido (═NH) substituent, or alternatively,        R^(23a) and R^(23b) are both hydrogen;

    -   when present, R^(24a) is selected from the group consisting of        hydrogen, —OH, and —NH₂;

    -   or alternatively, R^(24a) and R^(Y4) are taken together to form        a #—C(═O)—O— group, wherein # represent the attachment point to        the nitrogen atom bearing R^(Y4);

    -   when present, R^(24b) is hydrogen; and

    -   when present, R^(25a) and R^(25b) are both hydrogen;

    -   or alternatively, R^(25a), when present, and one R²⁹ of A⁴ are        taken together with the atoms connecting them to form a 5-6        membered heterocycloalkenyl optionally substituted with one or        more R²⁹ substituent, and R^(25b) is H;

    -   or alternatively, R^(25a), when present, R^(25b), when present,        and one R²⁹ of A⁴ are taken together with the atoms connecting        them to form a 5-6 membered heteroaryl optionally substituted        with one or more R²⁹ substituent;

    -   and further provided that one of (i), (ii), (iii) and (iv)        applies:

    -   (i) when m3 is 0 and n3 is 0, then:        -   X³ is CH and Y³ is NR^(Y3);        -   X⁴ is CH and Y⁴ is NR^(Y4);        -   R^(21a) and R^(21b) are taken together to form an oxo (═O)            substituent;        -   R^(23a) and R^(23b) are taken together to form an oxo (═O)            substituent;        -   A³ is a substituent of the formula (A³-b)

-   -   -   wherein            -   * represents the attachment point to the remainder of                the molecule;            -   Z⁷ is selected from the group consisting of                CR^(Z7-1)R^(Z7-2), NR^(Z7-2), O, S, and                —CR^(Z7-1)═CR^(Z7-1)—;                -   wherein                -   R^(Z7-1) is H or R²⁷; and                -   R^(Z7-2) is H or R²⁷;            -   Z⁸ is selected from the group consisting of                CR^(Z8-1)R^(Z8-2), NR^(Z8-2); O, S, and                CR^(Z8-1)═CR^(Z8-1)—;                -   wherein                -   R^(Z8-1) is H or R²⁷; and                -   R^(Z8-2) is H or R²⁷;            -   R²⁶ is hydrogen or R²⁷, or R²⁶ and R^(Z7-2) are taken                together to form a double bond between the carbon atom                bearing R²⁶ and Z⁷; R²⁷ is selected, independently at                each occurrence, from the group consisting of halogen,                C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OH, —O(C₁-C₆ alkyl),                —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆                haloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —NH(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂,                —NR^(27-a)R^(27-b), —CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl),                —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),                —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂,                —C(O)N(C₁-C₆ haloalkyl)₂, —C(O)NR^(27-a)R^(27-b),                —S(O)₂OH, —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆                haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl),                —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,                —S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(27-a)R^(27-b),                —OC(O)H, —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(27-a) and R^(27-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;            -   x3 is 0, 1, 2, 3, or 4;        -   A⁴ is a substituent of the formula (A⁴-b)

-   -   -   wherein            -   * represents the attachment point to the remainder of                the molecule;            -   Z¹⁰ is selected from the group consisting of                CR^(Z10-1)R^(Z10-2), O, S, and —CR^(Z10-1)═CR^(Z10-1)—;                -   wherein                -   R^(Z10-1) is H or R²⁹; and                -   R^(Z10-2) is H or R²⁹;            -   Z¹¹ is selected from the group consisting of                CR^(Z11-1)R^(Z11-2), NR^(Z11-2), O, S, and                CR^(Z11-1)═CR^(Z11-1)—;                -   wherein                -   R^(Z11-1) is H or R²⁹; and                -   R^(Z11-2) is H or R²⁹;            -   R²⁸ is hydrogen or R²⁹, or R²⁸ and R^(Z10-2) are taken                together to form a double bond between the carbon atom                bearing R²⁸ and Z¹⁰; R²⁹ is selected, independently at                each occurrence, from the group consisting of halogen,                C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OH, —O(C₁-C₆ alkyl),                —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆                haloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —NH(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂,                —NR^(29-a)R^(29-b), —CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl),                —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),                —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂,                —C(O)N(C₁-C₆ haloalkyl)₂, —C(O)NR^(29-a)R^(29-b),                —S(O)₂OH, —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆                haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl),                —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,                —S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(29-a)R^(29-b),                —OC(O)H, —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(29-a) and R^(29-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;            -   x4 is 0, 1, 2, 3, or 4; and        -   provided that A³ and A⁴ are not both simultaneously a moiety            selected from group consisting of:

wherein the * represents the attachment point to the remainder of themolecule;

-   -   (ii) when m3 is 0 and n3 is 1, then:        -   r2 is 1 or 2;        -   s2 is 1 or 2;        -   X³ is CH and Y³ is NR^(Y3);        -   R^(21a) and R^(21b) are taken together to form an oxo (═O)            substituent;        -   R^(24a) is selected from the group consisting of hydrogen,            —OH, and —NH₂;        -   A³ is a substituent of the formula (A³-b)

-   -   -   wherein            -   * represents the attachment point to the remainder of                the molecule; Z⁷ is selected from the group consisting                of CR^(Z7-1)R^(Z7-2); NR^(Z7-2); O, S, and                —CR^(Z7-1)═CR^(Z7-1)—;                -   wherein                -   R^(Z7-1) is H or R²⁷; and                -   R^(Z7-2) is H or R²⁷;            -   Z⁸ is selected from the group consisting of                CR^(Z8-1)R^(Z8-2), NR^(Z8-2), O, S, and                —CR^(Z8-1)═CR^(Z8-1)—;                -   wherein                -   R^(Z8-1) is H or R²⁷; and                -   R^(Z8-2) is H or R²⁷;            -   R²⁶ is hydrogen or R²⁷, or R²⁶ and R^(Z7-2) are taken                together to form a double bond between the carbon atom                bearing R²⁶ and Z⁷; R²⁷ is selected, independently at                each occurrence, from the group consisting of halogen,                C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OH, —O(C₁-C₆ alkyl),                —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆                haloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —NH(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂,                —NR^(27-a)R^(27-b), —CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl),                —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),                —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂,                —C(O)N(C₁-C₆ haloalkyl)₂, —C(O)NR^(27-a)R^(27-b),                —S(O)₂OH, —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆                haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl),                —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,                —S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(27-a)R^(27-b),                —OC(O)H, —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(27-a) and R^(27-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;            -   x3 is 0, 1, 2, 3, or 4;        -   A⁴ is C₆-C₁₀ aryl optionally substituted with one or more            R²⁹ substituent, or 5-10 membered heteroaryl optionally            substituted with one or more R²⁹ substituent;            -   R²⁹ is selected, independently at each occurrence, from                the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆                haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl),                —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,                —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆                alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(29-a)R^(29-b), —CN,                —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),                —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆                haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆                haloalkyl)₂, —C(O)NR^(29-a)R^(29-b), —S(O)₂OH,                —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),                —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆                haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆                haloalkyl)₂, —S(O)₂NR^(29-a)R^(29-b), —OC(O)H,                —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(29-a) and R^(29-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;        -   provided that when R^(23a) and R^(23b) are taken together to            form an oxo (═O) substituent, then R^(24a) is —OH or —NH₂;

    -   (iii) when m3 is 1 and n3 is 0, then:        -   X⁴ is CH and Y⁴ is NR^(Y4);        -   R^(21a) and R^(21b) are taken together to form an oxo (═O)            substituent or an imido (═NH) substituent;        -   R^(23a) and R^(23b) are taken together to form an oxo (═O)            substituent;        -   A³ is C₆-C₁₀ aryl optionally substituted with one or more            R²⁷ substituent, or 5-10 membered heteroaryl optionally            substituted with one or more R²⁷ substituent;            -   R²⁷ is selected, independently at each occurrence, from                the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆                haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl),                —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,                —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆                alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(27-a)R^(27-b), —CN,                —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),                —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆                haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆                haloalkyl)₂, —C(O)NR^(27-a)R^(27-b), —S(O)₂OH,                —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),                —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆                haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆                haloalkyl)₂, —S(O)₂NR^(27-a)R^(27-b), —OC(O)H,                —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(27-a) and R^(27-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;        -   A⁴ is a substituent of the formula (A⁴-b)

-   -   -   wherein            -   * represents the attachment point to the remainder of                the molecule; Z¹⁰ is selected from the group consisting                of CR^(Z10-1)R^(Z10-2), NR^(Z10-2), O, S, and                —CR^(Z10-1)═CR^(Z10-1)—;                -   wherein                -   R^(Z19-1) is H or R²⁹; and                -   R^(Z19-2) is H or R²⁹;            -   Z¹¹ is selected from the group consisting of                CR^(Z11-1)R^(Z11-2), NR^(Z11-2); O, S, and                —CR^(Z11-1)═CR^(Z11-1)—;                -   wherein                -   R^(Z11-1) is H or R²⁹; and                -   R^(Z11-2) is H or R²⁹;            -   R²⁸ is hydrogen or R²⁹, or R²⁸ and R^(Z10-2) are taken                together to form a double bond between the carbon atom                bearing R²⁸ and Z¹);            -   R²⁹ is selected, independently at each occurrence, from                the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆                haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl),                —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,                —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆                alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(29-a)R^(29-b), —CN,                —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),                —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆                haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆                haloalkyl)₂, —C(O)NR^(29-a)R^(29-b), —S(O)₂OH,                —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),                —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆                haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆                haloalkyl)₂, —S(O)₂NR^(29-a)R^(29-b), —OC(O)H,                —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(29-a) and R^(29-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;            -   x4 is 0, 1, 2, 3, or 4;

    -   (iv) when m3 is 1 and n3 is 1, then:        -   R^(21a) and R^(21b) are taken together to form an oxo (═O)            substituent or an imido (═NH) substituent;        -   A³ is C₆-C₁₀ aryl optionally substituted with one or more            R²⁷ substituent, or 5-10 membered heteroaryl optionally            substituted with one or more R²⁷ substituent;            -   R²⁷ is selected, independently at each occurrence, from                the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆                haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl),                —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,                —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆                alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(27-a)R^(27-b), —CN,                —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),                —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆                haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆                haloalkyl)₂, —C(O)NR^(27-a)R^(27-b), —S(O)₂OH,                —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),                —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆                haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆                haloalkyl)₂, —S(O)₂NR^(27-a)R^(27-b), —OC(O)H,                —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(27-a) and R^(27-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;        -   A⁴ is C₆-C₁₀ aryl optionally substituted with one or more            R²⁹ substituent, or 5-10 membered heteroaryl optionally            substituted with one or more R²⁹ substituent;            -   R²⁹ is selected, independently at each occurrence, from                the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆                haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl),                —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,                —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆                alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(29-a)R^(29-b), —CN,                —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),                —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆                haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆                haloalkyl)₂, —C(O)NR^(29-a)R^(29-b), —S(O)₂OH,                —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),                —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆                haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆                haloalkyl)₂, —S(O)₂NR^(29-a)R^(29-b), —OC(O)H,                —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(29-a) and R^(29-b) are taken together                    with the nitrogen atom            -   which bears them to form a 3-10 membered heterocycle;        -   provided that:            -   when one of X³ or X⁴ is N, then r2 is 1 or 2 and s2 is 1                or 2; and            -   when R^(23a) and R^(23b) are taken together to form an                oxo (═O) substituent, then R^(24a) is —OH or —NH₂.

In some embodiments the compound of formula (II) is a compound offormula (III):

wherein Y³, R^(Y3), Y⁴, R^(Y4), m3, n3, r2, s2, A³, Z⁷, R^(Z7-1),R^(Z7-2), Z⁸, R^(Z8-1), R^(Z8-2), Z⁹, x3, A⁴, Z¹⁰, R^(Z10-1), R^(Z10-2),Z¹¹, R^(Z11-1), R^(Z11-2), Z¹², x4, R^(17a), R^(18a), R^(18b), R^(19a),R^(19b), R^(20a), R^(20b), R^(21a), R^(21b), R^(22a), R^(22b), R^(23a),R^(23b), R^(24a), R^(24b), R^(25a), R^(25b), R²⁶, R²⁷, R²⁸, and R²⁹ areas defined in compounds of formula (II);

or a pharmaceutically acceptable salt thereof.

In some embodiments the compound of formula (II) is a compound offormula (IV):

wherein Y³, R^(Y3), m3, r2, s2, A³, Z⁷, R^(Z7-1), R^(Z7-2), Z⁸,R^(Z8-1), R^(Z8-2), Z⁹, x3, A⁴, Z¹⁰, R^(Z10-1), R^(Z10-2), R^(Z11-1),R^(Z11-2), Z¹², x4, R^(17a), R^(17b), R^(18a), R^(18b), R^(19a),R^(19b), R^(20a), R^(20b), R^(21a), R^(21b), R^(22a), R^(22b), R^(23a),R^(23b), R^(24a), R^(24b), R^(25a), R^(25b), R²⁶, R²⁷, R²⁸, and R²⁹ areas defined in compounds of formula (II);

or a pharmaceutically acceptable salt thereof.

In some embodiments the compound of formula (II) is a compound offormula (V):

wherein Y⁴, R^(Y4), n3, r2, s2, A³, Z⁷, R^(Z7-1), R^(Z7-2), Z⁸,R^(Z8-1), R^(Z8-2), Z⁹, x3, A⁴, Z¹⁰, R^(Z10-1), R^(Z10-2), R^(Z11-1),R^(Z11-2), Z¹², x4, R^(17a), R^(17b), R^(18a), R^(18b), R^(19a),R^(19b), R^(20a), R^(20b), R^(21a), R^(21b), R^(22a), R^(22b), R^(23a),R^(23b), R^(24a), R^(24b), R^(25a), R^(25b), R²⁶, R²⁷, R²⁸, and R²⁹ areas defined in compounds of formula (II);

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compounds of formula (II), (III), (IV), or(V), R^(17a) and R^(17b) are independently hydrogen or C₁-C₆ alkyl. Insome embodiments, R^(17a) and R^(17b) are both hydrogen. In someembodiments, R^(17a) and R^(17b) are both C₁-C₆ alkyl. In someembodiments, R^(17a) and R^(17b) are both methyl. In some embodiments,R^(17a) is hydrogen and R^(17b) is C₁-C₆ alkyl. In some embodiments,R^(17a) is hydrogen and R^(17b) is methyl.

In some embodiments of the compounds of formula (II), (III), (IV), or(V), R^(18a) and R^(18b) are independently hydrogen or C₁-C₆ alkyl. Insome embodiments, R^(18a) and R^(18b) are both hydrogen. In someembodiments, R^(18a) and R^(18b) are both C₁-C₆ alkyl. In someembodiments, R^(18a) and R^(18b) are both methyl. In some embodiments,R^(18a) is hydrogen and R^(18b) is C₁-C₆ alkyl. In some embodiments,R^(18a) is hydrogen and R^(18b) is methyl.

In some embodiments of the compounds of formula (II), (III), (IV), or(V), R^(17a), R^(17b), R^(18a), and R^(18b) are hydrogen.

In some embodiments of the compounds of formula (II), (III), (IV), or(V), R^(17a), R^(17b), R^(18a), and R^(18b) are independently C₁-C₆alkyl. In some embodiments, R^(17a), R^(17b), R^(18a), and R^(18b) aremethyl.

In some embodiments of the compounds of formula (II), (III), (IV), or(V), R^(17a) and R^(18a) are independently C₁-C₆ alkyl, and R^(17b) andR^(18b) are both hydrogen. R^(17a) and R^(18a) are both methyl, andR^(17b) and R^(18b) are both hydrogen.

In some embodiments of the compounds of formula (II), (III), (IV), or(V), R^(17a) and R^(18a) are taken together to form a C₁-C₆ alkylenemoiety, and R^(17a) and R^(18b) are both hydrogen. In some embodiments,R^(17a) and R^(18a) are taken together to form an ethylene (—CH₂—CH₂—)moiety, and R^(17b) and R^(18b) are both hydrogen. In some embodiments,R^(17a) and R^(18a) are taken together to form a propylene(—CH₂—CH₂—CH₂—) moiety, and R^(17b) and R^(18b) are both hydrogen.

In some embodiments of the compounds of formula (II), (III), (IV), or(V), r2 is 1 and s2 is 1. In some embodiments, R^(17a) and R^(17b) areindependently hydrogen or C₁-C₆ alkyl. In some embodiments, R^(17a) andR^(18a) are both hydrogen. In some embodiments, R^(17a) and R^(17b) areboth C₁-C₆ alkyl. In some embodiments, R^(17a) and R^(17b) are bothmethyl. In some embodiments, R^(17a) is hydrogen and R^(17b) is C₁-C₆alkyl. In some embodiments, R^(17a) is hydrogen and R^(17b) is methyl.In some embodiments, R^(18a) and R^(18b) are independently hydrogen orC₁-C₆ alkyl. In some embodiments, R^(18a) and R^(18b) are both hydrogen.In some embodiments, R^(18a) and R^(18b) are both C₁-C₆ alkyl. In someembodiments, R^(18a) and R^(18b) are both methyl. In some embodiments,R^(18a) is hydrogen and R^(18b) is C₁-C₆ alkyl. In some embodiments,R^(18a) is hydrogen and R^(18b) is methyl. In some embodiments, R^(17a),R^(17b), R^(18a), and R^(18b) are hydrogen. In some embodiments,R^(17a), R^(17b), R^(18a), and R^(18b) are independently C₁-C₆ alkyl. Insome embodiments, R^(17a), R^(17b), R^(18a), and R^(18b) are methyl. Insome embodiments, R^(17a) and R^(18a) are independently C₁-C₆ alkyl, andR^(17b) and R^(18b) are both hydrogen. R^(17a) and R^(18a) are bothmethyl, and R^(17b) and R^(18b) are both hydrogen. In some embodiments,R^(17a) and R^(18a) are taken together to form a C₁-C₆ alkylene moiety,and R^(17b) and R^(18b) are both hydrogen. In some embodiments, R^(17a)and R^(18a) are taken together to form an ethylene (—CH₂—CH₂—) moiety,and R^(17b) and R^(18b) are both hydrogen. In some embodiments, R^(17a)and R^(18a) are taken together to form a propylene (—CH₂—CH₂—CH₂—)moiety, and R^(17b) and R^(18b) are both hydrogen. In some embodiments,R^(19a) and R^(19b) are independently hydrogen or C₁-C₆ alkyl. In someembodiments, R^(19a) and R^(19b) are both hydrogen. In some embodiments,R^(19a) and R^(19b) are both C₁-C₆ alkyl. In some embodiments, R^(19a)and R^(19b) are both methyl. In some embodiments, R^(19a) is hydrogenand R^(19b) is C₁-C₆ alkyl. In some embodiments, R^(19a) is hydrogen andR^(19b) is methyl. In some embodiments, R^(20a) and R^(20b) areindependently hydrogen or C₁-C₆ alkyl. In some embodiments, R^(20a) andR^(20b) are both hydrogen. In some embodiments, R^(20a) and R^(20b) areboth C₁-C₆ alkyl. In some embodiments, R^(20a) and R^(20b) are bothmethyl. In some embodiments, R^(20a) is hydrogen and R^(20b) is C₁-C₆alkyl. In some embodiments, R^(20a) is hydrogen and R^(20b) is methyl.In some embodiments, R^(19a), R^(19b), R^(20a), and R^(20b) arehydrogen. In some embodiments, R^(19a), R^(19b), R^(20a), and R^(20b)are independently C₁-C₆ alkyl. In some embodiments, R^(19a), R^(19b),R^(20a), and R^(20b) are methyl. In some embodiments, R^(19a) areindependently C₁-C₆ alkyl, and R^(19b) and R^(20a) are both hydrogen. Insome embodiments, R^(19a) and R^(20a) are both methyl, and R^(19b) andR^(20b) are both hydrogen. In some embodiments, R^(19a) and R^(20a) aretaken together to form a C₁-C₆ alkylene moiety, and R^(19b) and R^(20b)are both hydrogen. In some embodiments, R^(19a) and R^(20a) are takentogether to form an ethylene (—CH₂—CH₂—) moiety, and R^(19b) and R^(20b)are both hydrogen. In some embodiments, R^(19a) and R^(20a) are takentogether to form a propylene (—CH₂—CH₂—CH₂—) moiety, and R^(19b) andR^(20b) are both hydrogen. In some embodiments, R^(17a) and R^(19a) aretaken together to form a C₁-C₆ alkylene moiety, and R^(17b) and R^(19b)are both hydrogen. In some embodiments, R^(17a) and R^(19a) are takentogether to form an ethylene (—CH₂—CH₂—) moiety, and R^(17b) and R^(19b)are both hydrogen. In some embodiments, R^(17a) and R^(19a) are takentogether to form a propylene (—CH₂—CH₂—CH₂—) moiety, and R^(17b) andR^(19b) are both hydrogen.

In some embodiments of the compounds of formula (II), (III), (IV), or(V), r2 is 2 and s2 is 0. In some embodiments, R^(17a) and R¹areindependently hydrogen or C₁-C₆ alkyl. In some embodiments, R^(17a) andR^(17b) are both hydrogen. In some embodiments, R^(17a) and R^(17b) areboth C₁-C₆ alkyl. In some embodiments, R^(17a) and R^(17b) are bothmethyl. In some embodiments, R^(17a) is hydrogen and R^(17b) is C₁-C₆alkyl. In some embodiments, R^(17a) is hydrogen and R^(17b) is methyl.In some embodiments, R^(18a) and R^(18b) are independently hydrogen orC₁-C₆ alkyl. In some embodiments, R^(18a) and R^(18b) are both hydrogen.In some embodiments, R^(18a) and R^(18b) are both C₁-C₆ alkyl. In someembodiments, R^(18a) and R^(18b) are both methyl. In some embodiments,R^(18a) is hydrogen and R^(18b) is C₁-C₆ alkyl. In some embodiments,R^(18a) is hydrogen and R^(18b) is methyl. In some embodiments, R^(17a),R^(17b), R^(18a), and R^(18b) are hydrogen. In some embodiments,R^(17a), R^(17b), R^(18a), and R^(18b) are independently C₁-C₆ alkyl. Insome embodiments, R^(17a), R^(17b), R^(18a), and R^(18b) are methyl. Insome embodiments, R^(17a) and R^(18a) are independently C₁-C₆ alkyl, andR^(17b) and R^(18b) are both hydrogen. R^(17a) and R^(18a) are bothmethyl, and R^(17b) and R^(18b) are both hydrogen. In some embodiments,R^(17a) and R^(18a) are taken together to form a C₁-C₆ alkylene moiety,and R^(17b) and R^(18b) are both hydrogen. In some embodiments, R^(17a)and R^(18a) are taken together to form an ethylene (—CH₂—CH₂—) moiety,and R^(17b) and R^(18b) are both hydrogen. In some embodiments, R^(17a)and R^(18a) are taken together to form a propylene (—CH₂—CH₂—CH₂—)moiety, and R^(11b) and R^(18b) are both hydrogen. In some embodiments,R^(19a) and R^(19b) are independently at each occurrence hydrogen orC₁-C₆ alkyl. In some embodiments, R^(19a) and R^(19b) are independentlyat each occurrence hydrogen or methyl. In some embodiments, R^(19a) andR^(19b) are both at each occurrence hydrogen. In some embodiments,R^(19a) and R^(19b) are both at each occurrence C₁-C₆ alkyl. In someembodiments, R^(19a) and R^(19b) are both at each occurrence methyl. Insome embodiments, R^(19a) is at each occurrence hydrogen and R^(19b) isat each occurrence C₁-C₆ alkyl. In some embodiments, R^(19a) is at eachoccurrence hydrogen and R^(19b) is at each occurrence methyl. In someembodiments, R^(19a) is at each occurrence hydrogen and R^(19b) is ateach occurrence methyl. In some embodiments, one R^(19a) is hydrogen andthe other R^(19a) is C₁-C₆ alkyl and R^(19b) is at each occurrencehydrogen. In some embodiments, one R^(19a) is hydrogen and the otherR^(19a) is methyl, and R^(19b) is at each occurrence hydrogen. In someembodiments, R^(19a) is at each occurrence hydrogen, one R^(19b) ishydrogen, and the other R^(19b) is C₁-C₆ alkyl. In some embodiments,R^(19a) is at each occurrence hydrogen, one R^(19b) is hydrogen, and theother R^(19b) is methyl. In some embodiments, R^(17a) and an R^(19a)moiety are taken together to form a C₁-C₆ alkylene moiety, and R^(17b)and the R^(19b) in the geminal position to the R^(19a) taken togetherwith R^(17a), are both hydrogen. In some embodiments, R^(17a) and anR^(19a) moiety are taken together to form an ethylene (—CH₂—CH₂—)moiety, and R^(17b) and the R^(19b) in the geminal position to theR^(19a) taken together with R^(17a), are both hydrogen. In someembodiments, R^(17a) and an R^(19a) moiety are taken together to form apropylene (—CH₂—CH₂—CH₂—) moiety, and R^(17b) and the R^(19b) in thegeminal position to the R^(19a) taken together with R^(17a), are bothhydrogen.

In some embodiments of the compounds of formula (II), (III), (IV), or(V), R²⁷, independently at each occurrence, is halogen. In someembodiments, R²⁷, independently at each occurrence, is selected from thegroup consisting of fluoro and chloro.

In some embodiments of the compounds of formula (II), (III), (IV), or(V), R²⁹, independently at each occurrence, is halogen. In someembodiments, R²⁹, independently at each occurrence, is selected from thegroup consisting of fluoro and chloro.

In some embodiments of the compounds of formula (II), (III), (IV), or(V):

-   -   m3 is 0 and n3 is 0;    -   X³ is CH and Y³ is NR^(Y3);    -   X⁴ is CH and Y⁴ is NR^(Y4);    -   R^(21a) and R^(21b) are taken together to form an oxo (═O)        substituent;    -   R^(23a) and R^(23b) are taken together to form an oxo (═O)        substituent;    -   A³ is a substituent of the formula (A³-b)

-   -   -   wherein            -   * represents the attachment point to the remainder of                the molecule;            -   Z⁷ is selected from the group consisting of                CR^(Z7-1)R^(Z7-2), NR^(Z7-2), O, S, and                —CR^(Z7-1)═CR^(Z7-1)—;                -   wherein                -   R^(Z7-1) is H or R²⁷; and                -   R^(Z7-2) is H or R²⁷;            -   Z⁸ is selected from the group consisting of                CR^(Z8-1)R^(Z8-2), NR^(Z8-2); O, S, and                —CR^(Z8-1)═CR^(Z8-1)—,                -   wherein                -   R^(Z8-1) is H or R²⁷; and                -   R^(Z8-2) is H or R²⁷;            -   R²⁶ is hydrogen or R²⁷, or R²⁶ and R^(Z7-2) are taken                together to form a double bond between the carbon atom                bearing R²⁶ and Z⁷;            -   R²⁷ is selected, independently at each occurrence, from                the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆                haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl),                —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,                —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆                alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(27-a)R^(27-b), —CN,                —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),                —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆                haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆                haloalkyl)₂, —C(O)NR^(27-a)R^(27-b), —S(O)₂OH,                —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),                —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆                haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆                haloalkyl)₂, —S(O)₂NR^(27-a)R^(27-b), —OC(O)H,                —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(27-a) and R^(27-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;            -   x3 is 0, 1, 2, 3, or 4;

    -   A⁴ is a substituent of the formula (A⁴-b)

-   -   -   wherein            -   * represents the attachment point to the remainder of                the molecule;            -   Z¹⁰ is selected from the group consisting of                CR^(Z10-1)R^(Z10-2), NR^(Z10-2), O, S, and                —CR^(Z10-1)═CR^(Z10-1)—;                -   wherein                -   R^(Z10-1) is H or R²⁹; and                -   R^(Z10-2) is H or R²⁹;            -   Z¹¹ is selected from the group consisting of                CR^(Z11-1)R^(Z11)-2, NR^(Z11-2), O, S, and                CR^(Z11-1)═CR^(Z11-1)—;                -   wherein                -   R^(Z11-1) is H or R²⁹; and                -   R^(Z11-2) is H or R²⁹;            -   R²⁸ is hydrogen or R²⁹, or R²⁸ and R^(Z10-2) are taken                together to form a double bond between the carbon atom                bearing R²⁸ and Z¹⁰;            -   R²⁹ is selected, independently at each occurrence, from                the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆                haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl),                —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,                —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆                alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(29-a)R^(29-b), —CN,                —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),                —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆                haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆                haloalkyl)₂, —C(O)NR^(29-a)R^(29-b), —S(O)₂OH,                —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),                —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆                haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆                haloalkyl)₂, —S(O)₂NR^(29-a)R^(29-b), —OC(O)H,                —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(29-a) and R^(29-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;            -   x4 is 0, 1, 2, 3, or 4; and

provided that A³ and A⁴ are not both simultaneously a moiety selectedfrom group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (II), (III), (IV), or(V), wherein m3 is 0 and n3 is 0, X³ is CH, Y³ is NR^(Y3), X⁴ is CH, Y⁴is NR^(Y4), R^(21a) and R^(21b) are taken together to form an oxo (═O)substituent, and R^(23a) and R^(23b) are taken together to form an oxo(═O) substituent; (A³-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A³-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A³-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A³-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (II), (III), (IV), or(V), wherein m3 is 0 and n3 is 0, X³ is CH, Y³ is NR^(Y3), X⁴ is CH, Y⁴is NR^(Y4), R^(21a) and R^(21b) are taken together to form an oxo (═O)substituent, and R^(23a) and R^(23b) are taken together to form an oxo(═O) substituent; (A⁴-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A⁴-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A⁴-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A⁴-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (II), (III), (IV), or(V):

-   -   m3 is 0 and n3 is 1;    -   r2 is 1 or 2;    -   s2 is 1 or 2;    -   X³ is CH and Y³ is NR^(Y3);    -   R^(21a) and R^(21b) are taken together to form an oxo (═O)        substituent;    -   R^(24a) is selected from the group consisting of hydrogen, —OH,        and —NH₂;    -   R^(25a) and R^(25b) are both hydrogen;    -   A³ is a substituent of the formula (A³-b)

-   -   -   wherein            -   * represents the attachment point to the remainder of                the molecule;            -   Z⁷ is selected from the group consisting of                CR^(Z7-1)R^(Z7-2); NR^(Z7-2); O, S, and                —CR^(Z7-1)═CR^(Z7-1)—;                -   wherein                -   R^(Z7-1) is H or R²⁷; and                -   R^(Z7-2) is H or R²⁷;            -   Z⁸ is selected from the group consisting of                CR^(Z8-1)R^(Z8-2), NR^(Z8-2); 0, S, and                CR^(Z8-1)═CR^(Z8-1)—;                -   wherein                -   R^(Z8-1) is H or R²⁷; and                -   R^(Z8-2) is H or R²⁷;            -   R²⁶ is hydrogen or R²⁷, or R²⁶ and R^(Z7-2) are taken                together to form a double bond between the carbon atom                bearing R²⁶ and Z⁷;            -   R²⁷ is selected, independently at each occurrence, from                the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆                haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl),                —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,                —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆                alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(27-a)R^(27-b), —CN,                —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),                —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆                haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆                haloalkyl)₂, —C(O)NR^(27-a)R^(27-b), —S(O)₂OH,                —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),                —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆                haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆                haloalkyl)₂, —S(O)₂NR^(27-a)R^(27-b), —OC(O)H,                —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(27-a) and R^(27-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;            -   x3 is 0, 1, 2, 3, or 4; and

    -   A⁴ is C₆-C₁₀ aryl optionally substituted with one or more R²⁹        substituent, or 5-10 membered heteroaryl optionally substituted        with one or more R²⁹ substituent;        -   R²⁹ is selected, independently at each occurrence, from the            group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl,            —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆            alkyl), —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl),            —NH(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆            haloalkyl)₂, —NR^(29-a)R^(29-b), —CN, —C(O)OH, —C(O)O(C₁-C₆            alkyl), —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆            alkyl), —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂,            —C(O)N(C₁-C₆ haloalkyl)₂, —C(O)NR^(29-a)R^(29-b), —S(O)₂OH,            —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂,            —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ haloalkyl),            —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ haloalkyl)₂,            —S(O)₂NR^(29-a)R^(29-b), —OC(O)H, —OC(O)(C₁-C₆ alkyl),            —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl),            —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆            alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆            haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆            haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆            haloalkyl), —OS(O)₂(C₁-C₆ alkyl), —OS(O)₂(C₁-C₆ haloalkyl),            —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆ haloalkyl),            —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆            alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆            alkyl), and —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ haloalkyl);            -   wherein R^(29-a) and R^(29-b) are taken together with                the nitrogen atom which bears them to form a 3-10                membered heterocycle.

In some embodiments of the compounds of formula (II), (III), (IV), or(V), wherein m3 is 0, n3 is 1, r2 is 1 or 2, s2 is 1 or 2, X³ is CH, Y³is NR^(Y3), R^(21a) and R^(21b) are taken together to form an oxo (═O)substituent, R^(24a) is selected from the group consisting of hydrogen,—OH, and —NH₂, and R^(25a) and R^(25b) are both hydrogen; X⁴ is CH. Insome embodiments, Y⁴ is a bond. In some embodiments, Y⁴ is a NR^(Y4). Insome embodiments, R^(Y4) is hydrogen. In some embodiments, R^(Y4) isC₁-C₆ alkyl. In some embodiments, R^(Y4) is methyl. In some embodiments,R^(Y4) is ethyl. In some embodiments, Y⁴ is a O. In some embodiments,R^(23a) and R^(23b) are taken together to form an oxo (═O) substituentand R^(24a) is —OH or —NH₂. In some embodiments, R^(24a) is —OH. In someembodiments, R^(24a) is —NH₂. In some embodiments, R^(23a) and R^(23b)are taken together to form an imido (═NH) substituent. In someembodiments, R^(24a) is hydrogen. In some embodiments, R^(24a) is —OH.In some embodiments, R^(24a) is NH₂.

In some embodiments of the compounds of formula (II), (III), (IV), or(V), wherein m3 is 0, n3 is 1, r2 is 1 or 2, s2 is 1 or 2, X³ is CH, Y³is NR^(Y3), R^(21a) and R^(21b) are taken together to form an oxo (═O)substituent, R^(24a) is selected from the group consisting of hydrogen,—OH, and —NH₂, and R^(25a) and R^(25b) are both hydrogen; X⁴ is N. Insome embodiments, R^(23a) and R^(23b) are taken together to form an oxo(═O) substituent and R^(24a) is —OH or —NH₂. In some embodiments,R^(24a) is —OH. In some embodiments, R^(24a) is NH₂. In someembodiments, R^(23a) and R^(23b) are taken together to form an imido(═NH) substituent. In some embodiments, R^(24a) is hydrogen. In someembodiments, R^(24a) is —OH. In some embodiments, R^(24a) is NH₂. Insome embodiments, R^(23a) and R^(23b) are both hydrogen. In someembodiments, R^(24a) is hydrogen. In some embodiments, R^(24a) is —OH.In some embodiments, R^(24a) is NH₂.

In some embodiments of the compounds of formula (II), (III), (IV), or(V), wherein m3 is 0, n3 is 1, r2 is 1 or 2, s2 is 1 or 2, X³ is CH, Y³is NR^(Y3), R^(21a) and R^(21b) are taken together to form an oxo (═O)substituent, R^(24a) is selected from the group consisting of hydrogen,—OH, and —NH₂, and R^(25a) and R^(25b) are both hydrogen; (A³-b) isselected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A³-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A³-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A³-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (II), (III), (IV), or(V), wherein m3 is 0, n3 is 1, r2 is 1 or 2, s2 is 1 or 2, X³ is CH, Y³is NR^(Y3), R^(21a) and R^(21b) are taken together to form an oxo (═O)substituent, R^(24a) is selected from the group consisting of hydrogen,—OH, and —NH₂, and R^(25a) and R^(25b) are both hydrogen; A⁴ is C₆-C₁₀aryl optionally substituted with one or more R²⁹ substituent. In someembodiments, A⁴ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (II), (III), (IV), or(V), wherein m3 is 0, n3 is 1, r2 is 1 or 2, s2 is 1 or 2, X³ is CH, Y³is NR^(Y3), R^(21a) and R^(21b) are taken together to form an oxo (═O)substituent, R^(24a) is selected from the group consisting of hydrogen,—OH, and —NH₂, and R^(25a) and R^(25b) are both hydrogen; A⁴ is 5-10membered heteroaryl optionally substituted with one or more R²⁹substituent. In some embodiments, A⁴ is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (II), (III), (IV), or(V):

-   -   m3 is 1 and n3 is 0;    -   X⁴ is CH and Y⁴ is NR^(Y4);    -   R^(21a) and R^(21b) are taken together to form an oxo (═O)        substituent or an imido (═NH)    -   substituent;    -   R^(23a) and R^(23b) are taken together to form an oxo (═O)        substituent;    -   A³ is C₆-C₁₀ aryl optionally substituted with one or more R²⁷        substituent, or 5-10 membered heteroaryl optionally substituted        with one or more R²⁷ substituent;        -   R²⁷ is selected, independently at each occurrence, from the            group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl,            —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆            alkyl), —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl),            —NH(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆            haloalkyl)₂, —NR^(27-a)R^(27-b), —CN, —C(O)OH, —C(O)O(C₁-C₆            alkyl), —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆            alkyl), —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂,            —C(O)N(C₁-C₆ haloalkyl)₂, —C(O)NR^(27-a)R^(27-b), —S(O)₂OH,            —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂,            —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ haloalkyl),            —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ haloalkyl)₂,            —S(O)₂NR^(27-a)R^(27-b), —OC(O)H, —OC(O)(C₁-C₆ alkyl),            —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl),            —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆            alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆            haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆            haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆            haloalkyl), —OS(O)₂(C₁-C₆ alkyl), —OS(O)₂(C₁-C₆ haloalkyl),            —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆ haloalkyl),            —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆            alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆            alkyl), and —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ haloalkyl);            -   wherein R^(27-a) and R^(27-b) are taken together with                the nitrogen atom which bears them to form a 3-10                membered heterocycle;    -   A⁴ is a substituent of the formula (A⁴-b)

-   -   -   wherein            -   * represents the attachment point to the remainder of                the molecule;            -   Z¹⁰ is selected from the group consisting of                CR^(Z10-1)R^(Z10-2), NR^(Z10-2), O, S, and                —CR^(Z10-1)═CR^(Z10-1)—,                -   wherein                -   R^(Z10-1) is H or R²⁹; and                -   R^(Z10-2) is H or R²⁹;            -   Z¹¹ is selected from the group consisting of                CR^(Z11-1)R^(Z11-2), NR^(Z11-2), O, S, and                —CR^(Z11-1)═CR^(Z11-1)—,                -   wherein                -   R^(Z11-1) is H or R²⁹; and                -   R^(Z11-2) is H or R²⁹;            -   R²⁸ is hydrogen or R²⁹, or R²⁸ and R^(Z19-2) are taken                together to form a double bond between the carbon atom                bearing R²⁸ and Z¹⁰;            -   R²⁹ is selected, independently at each occurrence, from                the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆                haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl),                —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,                —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆                alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(29-a)R^(29-b), —CN,                —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),                —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆                haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆                haloalkyl)₂, —C(O)NR^(29-a)R^(29-b), —S(O)₂OH,                —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),                —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆                haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆                haloalkyl)₂, —S(O)₂NR^(29-a)R^(29-b), —OC(O)H,                —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(29-a) and R^(29-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;            -   x4 is 0, 1, 2, 3, or 4.

In some embodiments of the compounds of formula (II), (III), (IV), or(V), wherein m3 is 1, n3 is 0, X⁴ is CH, Y⁴ is NR^(Y4), R^(21a) andR^(21b) are taken together to form an oxo (═O) substituent or an imido(═NH) substituent, and R^(23a) and R^(23b) are taken together to form anoxo (═O) substituent; X³ is CH. In some embodiments, Y³ is a bond. Insome embodiments, Y³ is a NR^(Y3). In some embodiments, R^(Y3) ishydrogen. In some embodiments, R^(Y3) is C₁-C₆ alkyl. In someembodiments, R^(Y3) is methyl. In some embodiments, R^(Y3) is ethyl. Insome embodiments, Y³ is a O. In some embodiments, X³ is N. In someembodiments, R^(21a) and R^(21b) are taken together to form an oxo (═O)substituent. In some embodiments, R^(21a) and R^(21b) are taken togetherto form an imido (═NH) substituent.

In some embodiments of the compounds of formula (II), (III), (IV), or(V), wherein m3 is 1, n3 is 0, X⁴ is CH, Y⁴ is NR^(Y4), R^(21a) andR^(21b) are taken together to form an oxo (═O) substituent or an imido(═NH) substituent, and R^(23a) and R^(23b) are taken together to form anoxo (═O) substituent; A³ is C₆-C₁₀ aryl optionally substituted with oneor more R²⁷ substituent. In some embodiments, A³ is selected from thegroup consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (II), (III), (IV), or(V), wherein m3 is 1, n3 is 0, X⁴ is CH, Y⁴ is NR^(Y4), R^(21a) andR^(21b) are taken together to form an oxo (═O) substituent or an imido(═NH) substituent, and R^(23a) and R^(23b) are taken together to form anoxo (═O) substituent; A³ is 5-10 membered heteroaryl optionallysubstituted with one or more R²⁷ substituent. In some embodiments, A³ isselected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (II), (III), (IV), or(V), wherein m3 is 1, n3 is 0, X⁴ is CH, Y⁴ is NR^(Y4), R^(21a) andR^(21b) are taken together to form an oxo (═O) substituent or an imido(═NH) substituent, and R^(23a) and R^(23b) are taken together to form anoxo (═O) substituent; (A⁴-b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A⁴-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A⁴-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A⁴-b) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (II), (III), (IV), or(V):

-   -   m3 is 1 and n3 is 1;    -   R^(21a) and R^(21b) are taken together to form an oxo (═O)        substituent or an imido (═NH) substituent;    -   A³ is C₆-C₁₀ aryl optionally substituted with one or more R²⁷        substituent, or 5-10 membered heteroaryl optionally substituted        with one or more R²⁷ substituent;        -   R²⁷ is selected, independently at each occurrence, from the            group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl,            —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆            alkyl), —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl),            —NH(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆            haloalkyl)₂, —NR^(27-a)R^(27-b), —CN, —C(O)OH, —C(O)O(C₁-C₆            alkyl), —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆            alkyl), —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂,            —C(O)N(C₁-C₆ haloalkyl)₂, —C(O)NR^(27-a)R^(27-b), —S(O)₂OH,            —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂,            —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ haloalkyl),            —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ haloalkyl)₂,            —S(O)₂NR^(27-a)R^(27-b), —OC(O)H, —OC(O)(C₁-C₆ alkyl),            —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl),            —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆            alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆            haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆            haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆            haloalkyl), —OS(O)₂(C₁-C₆ alkyl), —OS(O)₂(C₁-C₆ haloalkyl),            —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆ haloalkyl),            —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆            alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆            alkyl), and —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ haloalkyl);            -   wherein R^(27-a) and R^(27-b) are taken together with                the nitrogen atom which bears them to form a 3-10                membered heterocycle;    -   A⁴ is C₆-C₁₀ aryl optionally substituted with one or more R²⁹        substituent, or 5-10 membered heteroaryl optionally substituted        with one or more R²⁹ substituent;        -   R²⁹ is selected, independently at each occurrence, from the            group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl,            —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆            alkyl), —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl),            —NH(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆            haloalkyl)₂, —NR^(29-a)R^(29-b), —CN, —C(O)OH, —C(O)O(C₁-C₆            alkyl), —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆            alkyl), —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂,            —C(O)N(C₁-C₆ haloalkyl)₂, —C(O)NR^(29-a)R^(29-b), —S(O)₂OH,            —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂,            —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ haloalkyl),            —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ haloalkyl)₂,            —S(O)₂NR^(29-a)R^(29-b), —OC(O)H, —OC(O)(C₁-C₆ alkyl),            —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl),            —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆            alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆            haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆            haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆            haloalkyl), —OS(O)₂(C₁-C₆ alkyl), —OS(O)₂(C₁-C₆ haloalkyl),            —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆ haloalkyl),            —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆            alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆            alkyl), and —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ haloalkyl);            -   wherein R^(29-a) and R^(29-b) are taken together with                the nitrogen atom which bears them to form a 3-10                membered heterocycle;    -   provided that:    -   when one of X³ or X⁴ is N, then r2 is 1 or 2 and s2 is 1 or 2;        and    -   when R^(23a) and R^(23b) are taken together to form an oxo (═O)        substituent, then R^(24a) is —OH or —NH₂.

In some embodiments of the compounds of formula (II), (III), (IV), or(V), wherein m3 is 1, n3 is 1, and R^(21a) and R^(21b) are takentogether to form an oxo (═O) substituent or an imido (═NH) substituent;X³ is CH. In some embodiments, Y³ is a bond. In some embodiments, Y³ isa NR^(Y3). In some embodiments, R^(Y3) is hydrogen. In some embodiments,R^(Y3) is C₁-C₆ alkyl. In some embodiments, R^(Y3) is methyl. In someembodiments, R^(Y3) is ethyl. In some embodiments, Y³ is a O.

In some embodiments of the compounds of formula (II), (III), (IV), or(V), wherein m3 is 1, n3 is 1, and R^(21a) and R^(21b) are takentogether to form an oxo (═O) substituent or an imido (═NH) substituent;X³ is N. In some embodiments, R^(21a) and R^(21b) are taken together toform an oxo (═O) substituent. In some embodiments, R^(21a) and R^(21b)are taken together to form an imido (═NH) substituent.

In some embodiments of the compounds of formula (II), (III), (IV), or(V), wherein m3 is 1, n3 is 1, and R^(21a) and R^(21b) are takentogether to form an oxo (═O) substituent or an imido (═NH) substituent;X⁴ is CH. In some embodiments, Y⁴ is a bond. In some embodiments, Y⁴ isa NR^(Y4). In some embodiments, R^(Y4) is hydrogen. In some embodiments,R^(Y4) is C₁-C₆ alkyl. In some embodiments, R^(Y4) is methyl. In someembodiments, R^(Y4) is ethyl. In some embodiments, Y⁴ is a O. In someembodiments, R^(23a) and R^(23b) are taken together to form an oxo (═O)substituent and R^(24a) is —OH or —NH₂. In some embodiments, R^(24a) is—OH. In some embodiments, R^(24a) is —NH₂. In some embodiments, R^(23a)and R^(23b) are taken together to form an imido (═NH) substituent. Insome embodiments, R^(24a) is hydrogen. In some embodiments, R^(24a) is—OH. In some embodiments, R^(24a) is —NH₂. In some embodiments, R^(23a)and R^(23b) are both hydrogen. In some embodiments, R^(24a) is hydrogen.In some embodiments, R^(24a) is —OH. In some embodiments, R^(24a) is—NH₂.

In some embodiments of the compounds of formula (II), (III), (IV), or(V), wherein m3 is 1, n3 is 1, and R^(21a) and R^(21b) are takentogether to form an oxo (═O) substituent or an imido (═NH) substituent;X⁴ is N. In some embodiments, R^(23a) and R^(23b) are taken together toform an oxo (═O) substituent and R^(24a) is —OH or —NH₂. In someembodiments, R^(24a) is —OH. In some embodiments, R^(24a) is NH₂. Insome embodiments, R^(23a) and R^(23b) are taken together to form animido (═NH) substituent. In some embodiments, R^(24a i)s hydrogen. Insome embodiments, R^(24a) is —OH. In some embodiments, R^(24a) is —NH₂.In some embodiments, R^(23a) and R^(23b) are both hydrogen. In someembodiments, R^(24a i)s hydrogen. In some embodiments, R^(24a) is —OH.In some embodiments, R^(24a) is —NH₂.

In some embodiments of the compounds of formula (II), (III), (IV), or(V), wherein m3 is 1, n3 is 1, and R^(21a) and R^(21b) are takentogether to form an oxo (═O) substituent or an imido (═NH) substituent;A³ is C₆-C₁₀ aryl optionally substituted with one or more R²⁷substituent. In some embodiments, A³ is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (II), (III), (IV), or(V), wherein m3 is 1, n3 is 1, and R^(21a) and R^(21b) are takentogether to form an oxo (═O) substituent or an imido (═NH) substituent;A³ is 5-10 membered heteroaryl optionally substituted with one or moreR²⁷ substituent. In some embodiments, A³ is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (II), (III), (IV), or(V), wherein m3 is 1, n3 is 1, and R^(21a) and R^(21b) are takentogether to form an oxo (═O) substituent or an imido (═NH) substituent;A⁴ is C₆-C₁₀ aryl optionally substituted with one or more R²⁹substituent. In some embodiments, A⁴ is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (II), (III), (IV), or(V), wherein m3 is 1, n3 is 1, and R^(21a) and R^(21b) are takentogether to form an oxo (═O) substituent or an imido (═NH) substituent;A⁴ is 5-10 membered heteroaryl optionally substituted with one or moreR²⁹ substituent. In some embodiments, A⁴ is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In one aspect, provided is a compound of formula (X-1):

or a pharmaceutically acceptable salt thereof;

-   -   wherein:    -   R³⁰ and R³¹ are, independently of each other and independently        at each occurrence, halogen;    -   x5 and x6 are independently of each other 0, 1, 2, 3, 4 or 5;    -   Q¹ is selected from the group consisting of:

-   -   wherein * represents the point of attachment to the

-   -   -   moiety, and # represents the point of attachment to the

-   -   -   moiety; and

    -   R³² and R³³ are both hydrogen, or R³² and R³³ are taken together        to form an oxo (═O) substituent.

In some embodiments of the compounds of formula (X-1), Q¹ is

and R³² and R³³ are both hydrogen.

In some embodiments of the compounds of formula (X-1), Q¹ is

and R³² and R³³ are taken together to form an oxo (═O) substituent.

In some embodiments of the compounds of formula (X-1), Q¹ is

In some embodiments of the compounds of formula (X-1), Q¹ is

In some embodiments of the compounds of formula (X-1), Q¹ is

In some embodiments of the compounds of formula (X-1), Q¹ is

In some embodiments of the compounds of formula (X-1), R³⁰ and R³¹ are,independently of each other and independently at each occurrence,selected from fluoro and chloro.

In some embodiments of the compounds of formula (X-1), x5 and x6 areboth 1. In some embodiments, x5 is 1 and x6 is 2. In some embodiments,x5 is 2 and x6 is 1. In some embodiments, x5 and x6 are both 2.

In one aspect, provided is a compound of formula (X-2):

or a pharmaceutically acceptable salt thereof;

-   -   wherein:    -   R³⁴ and R³⁵ are, independently of each other and independently        at each occurrence, halogen;    -   x7 and x8 are, independently of each other, 0, 1, 2, 3, 4, or 5;    -   A⁵ is a 5-12 membered heteroaryl;    -   Q² is selected from the group consisting of:

-   -   wherein * represents the point of attachment to the

moiety, and # represents the point of attachment to the

moiety;

-   -   R³⁶ and R³⁷ are both hydrogen, or R³⁶ and R³⁷ are taken together        to form an oxo (═O) substituent;    -   R³⁸ and R³⁹ are both hydrogen, or R³⁸ and R³⁹ are taken together        to form a propylene (—CH₂—CH₂—CH₂—) moiety; and    -   T¹ is —CR⁴⁰R⁴¹— or S(═O)₂—, wherein R⁴⁰ is selected from the        group consisting of hydrogen, —OH, and —NH₂; and R⁴¹ is        hydrogen.

In some embodiments of the compounds of formula (X-2), Q² is

and R³⁶ and R³⁷ are both hydrogen.

In some embodiments of the compounds of formula (X-2), Q² is

and R³⁶ and R³⁷ are taken together to form an oxo (═O) substituent.

In some embodiments of the compounds of formula (X-2), Q² is

and R³⁶ and R³⁷ are both hydrogen.

In some embodiments of the compounds of formula (X-2), Q² is

and R³⁶ and R³⁷ are taken together to form an oxo (═O) substituent.

In some embodiments of the compounds of formula (X-2), Q² is

and R³⁸ and R³⁹ are both hydrogen. In some embodiments, T¹ is —CR⁴⁰R⁴¹—.In some embodiments, T¹ is —CR⁴⁰R⁴¹—, and R⁴⁰ is selected from the groupconsisting of hydrogen, —OH, and —NH₂; and R⁴¹ is hydrogen. In someembodiments, T¹ is CR⁴⁰R⁴¹—, R⁴⁰ is hydrogen and R⁴¹ is hydrogen. Insome embodiments, T¹ is —CR⁴⁰R⁴¹—, R⁴⁰ is —OH, and R⁴¹ is hydrogen. Insome embodiments, T¹ is —CR⁴⁰R⁴¹—, R⁴⁰ is —NH₂, and R⁴¹ is hydrogen. Inother embodiments, T¹ is S(═O)₂—.

In some embodiments of the compounds of formula (X-2), Q² is

and R³⁸ and R³⁹ are taken together to form a propylene (—CH₂—CH₂—CH₂—)moiety. In some embodiments, T¹ is CR⁴⁰R⁴¹—. In some embodiments, T¹ isCR⁴⁰R⁴¹—, and R⁴⁰ is selected from the group consisting of hydrogen,—OH, and —NH₂; and R⁴¹ is hydrogen. In some embodiments, T¹ is—CR⁴⁰R⁴¹—, R⁴⁰ is hydrogen and R⁴¹ is hydrogen. In some embodiments, T¹is —CR⁴⁰R⁴¹—, R⁴⁰ is —OH, and R⁴¹ is hydrogen. In some embodiments, T¹is —CR⁴⁰R⁴¹—, R⁴⁰ is —NH₂, and R⁴¹ is hydrogen. In other embodiments, T¹is S(═O)₂—.

In some embodiments of the compounds of formula (X-2), R³⁴ and R³⁵ are,independently of each other and independently at each occurrence,selected from fluoro and chloro.

In some embodiments of the compounds of formula (X-1), x7 and x8 areboth 1. In some embodiments, x7 is 1 and x8 is 2. In some embodiments,x7 is 2 and x8 is 1. In some embodiments, x7 and x8 are both 2.

In one aspect, provided is a compound of formula (X-3):

or a pharmaceutically acceptable salt thereof;

-   -   wherein:    -   R⁴² and R⁴³are, independently of each other and independently at        each occurrence, halogen;    -   x9 and x10 are, independently of each other, 0, 1, 2, 3, 4, or        5;    -   R⁴⁴ and R⁴⁵ are both hydrogen, or R⁴⁴ and R⁴⁵ are taken together        to form an ethylene (—CH₂—CH₂—) moiety;    -   A⁶ is a 5-12 membered heteroaryl;    -   A⁷ is C₆-C₁₀ aryl or 5-12 membered heteroaryl;    -   Q³ is selected from the group consisting of:

-   -   wherein * represents the point of attachment to the

moiety, and # represents the point of attachment to the

moiety; and

-   -   provided that one of (i) or (ii) applies:        -   (i) q3 is 0, Q³ is

and A⁷ is 5-12 membered heteroaryl;

-   -   -   (ii) q3 is 1, Q³ is

and A⁷ is C₆-C₁₀ aryl.

In some embodiments of the compounds of formula (X-3), q3 is 0, Q³ is

and A⁷ is 5-12 membered heteroaryl.

In some embodiments of the compounds of formula (X-3), q3 is 1, Q³ is

and A⁷ is C₆-C₁₀ aryl. In some embodiments of the compounds of formula(X-3), q3 is 1, Q³ is

and A⁷ is C₆-C₁₀ aryl. In some embodiments of the compounds of formula(X-3), q3 is 1, Q³ is

and A⁷ is C₆-C₁₀ aryl. In some embodiments, A⁷ is phenyl.

In some embodiments of the compounds of formula (X-3), R⁴⁴ and R⁴⁵ areboth hydrogen. In some embodiments of the compounds of formula (X-3),R⁴⁴ and R⁴⁵ are taken together to form an ethylene (—CH₂—CH₂—) moiety.

In some embodiments of the compounds of formula (X-3), R⁴² and R⁴³ are,independently of each other and independently at each occurrence,selected from fluoro and chloro.

In some embodiments of the compounds of formula (X-3), x9 and x10 areboth 1. In some embodiments, x9 is 1 and x10 is 2. In some embodiments,x9 is 2 and x10 is 1. In some embodiments, x9 and x10 are both 2.

In one aspect, provided is a compound of formula (X-4):

or a pharmaceutically acceptable salt thereof;

-   -   wherein:    -   R⁴⁶ and R⁴⁷ are, independently of each other and independently        at each occurrence, halogen;    -   x11 and x12 are, independently of each other, 0, 1, 2, 3, 4, or        5;    -   R⁴⁸ is hydrogen or —OH;    -   Q⁴ is selected from the group consisting of:

-   -   wherein * represents the point of attachment to the

moiety, and # represents the point of attachment to the

-   -   R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, R⁶⁰, R⁶¹,        R⁶², R⁶³, and R⁶⁴ are, independently of each other, hydrogen or        C₁-C₆ alkyl.

In some embodiments of the compounds of formula (X-4), Q⁴ is

In some embodiments, R⁴⁹ and R⁵¹ are both C₁-C₆ alkyl, and R⁵⁰, R⁵²,R⁵³, R⁵⁴, R⁵⁵, and R⁵⁶ are all hydrogen. In some embodiments, R⁴⁹ andR⁵¹ are both methyl, and R⁵⁰, R⁵², R⁵³, R⁵⁴, R⁵⁵, and R⁵⁶ are allhydrogen. In some embodiments, R⁵³ and R⁵⁵ are both C₁-C₆ alkyl, andR⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵⁴, and R⁵⁶ are all hydrogen. In some embodiments,R⁵³ and R⁵⁵ are both methyl, and R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵⁴, and R⁵⁶ areall hydrogen. In some embodiments, R⁴⁹, R⁵⁰, R⁵¹, and R⁵² are all C₁-C₆alkyl, R⁵³, R⁵⁴, R⁵⁵, and R⁵⁶ are all hydrogen. In some embodiments,R⁴⁹, R⁵⁰, R⁵¹, and R⁵² are all methyl, R⁵³, R⁵⁴, R⁵⁵, and R⁵⁶ are allhydrogen. In some embodiments, R⁴⁹, R⁵⁰, R⁵¹, and R⁵² are all hydrogen,R⁵³, R⁵⁴, R⁵⁵, and R⁵⁶ are all C₁-C₆ alkyl. In some embodiments, R⁴⁹,R⁵⁰, R⁵¹, and R⁵² are all hydrogen, R⁵³, R⁵⁴, R⁵⁵, and R⁵⁶ are allmethyl. In some embodiments, R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, and R⁵⁶are all hydrogen.

In some embodiments of the compounds of formula (X-4), Q⁴ is

In some embodiments, R⁵⁷, R⁵⁸, R⁵⁹, and R⁶⁰ are all C₁-C₆ alkyl. In someembodiments, R⁵⁷, R⁵⁸, R⁵⁹, and R⁶⁰ are all methyl. In some embodiments,R⁵⁷ and R⁵⁹ are both C₁-C₆ alkyl, and R⁵⁸ and R⁶⁰ are both hydrogen. Insome embodiments, R⁵⁷ and R⁵⁹ are both methyl, and R⁵⁸ and R⁶⁰ are bothhydrogen. In some embodiments, R⁵⁷, R⁵⁸, R⁵⁹, and R⁶⁰ are all hydrogen.

In some embodiments of the compounds of formula (X-4), Q⁴ is

In some embodiments, R⁶¹, R⁶², R⁶³, and R⁶⁴ are all C₁-C₆ alkyl. In someembodiments, R⁶¹, R⁶², R⁶³, and R⁶⁴ are all methyl. In some embodiments,R⁶¹ and R⁶³ are both C₁-C₆ alkyl, and R⁶² and R⁶⁴ are both hydrogen. Insome embodiments, R⁶¹ and R⁶³ are both methyl, and R⁶² and R⁶⁴ are bothhydrogen. In some embodiments, R⁶¹, R⁶², R⁶³, and R⁶⁴ are all hydrogen.

In some embodiments of the compounds of formula (X-4), R⁴⁸ is hydrogen.

In some embodiments of the compounds of formula (X-4), R⁴⁸ is —OH.

In some embodiments of the compounds of formula (X-4), R⁴⁶ and R⁴⁷ are,independently of each other and independently at each occurrence,selected from fluoro and chloro.

In some embodiments of the compounds of formula (X-4), x11 and x12 areboth 1. In some embodiments, x11 is 1 and x12 is 2. In some embodiments,x11 is 2 and x12 is 1. In some embodiments, x11 and x12 are both 2.

In one aspect, provided is a compound of formula (X-5):

or a pharmaceutically acceptable salt thereof;

-   -   wherein:    -   R⁶⁵ and R⁶⁶ are, independently of each other and independently        at each occurrence, halogen;    -   x13 and x14 are, independently of each other, 0, 1, 2, 3, 4, or        5;    -   Q⁵ is selected from the group consisting of:

-   -   wherein * represents the point of attachment to the

and # represents the point of attachment to the

-   -   R⁶⁷ and R⁶⁸ are both hydrogen, or R⁶⁷ and R⁶⁸ are taken together        to form an imino (═NH) substituent; and    -   R⁶⁹ is hydrogen or —NH₂.

In some embodiments of the compounds of formula (X-5), Q⁵ is

In some embodiments of the compounds of formula (X-5), Q⁵ is

In some embodiments, R⁶⁷ and R⁶⁸ are both hydrogen, and R⁶⁹ is hydrogenor NH₂. In some embodiments, R⁶⁷ and R⁶⁸ are both hydrogen, and R⁶⁹ ishydrogen. In some embodiments, R⁶⁷ and R⁶⁸ are both hydrogen, and R⁶⁹ isNH₂. In some embodiments, R⁶⁷ and R⁶⁸ are taken together to form animino (═NH) substituent, and R⁶⁹ is hydrogen or NH₂. In someembodiments, R⁶⁷ and R⁶⁸ are taken together to form an imino (═NH)substituent, and R⁶⁹ is hydrogen. In some embodiments, R⁶⁷ and R⁶⁸ aretaken together to form an imino (═NH) substituent, and R⁶⁹ is —NH₂.

In some embodiments of the compounds of formula (X-5), R⁶⁵ and R⁶⁶ are,independently of each other and independently at each occurrence,selected from fluoro and chloro.

In some embodiments of the compounds of formula (X-5), x13 and x14 areboth 1. In some embodiments, x13 is 1 and x14 is 2. In some embodiments,x13 is 2 and x14 is 1. In some embodiments, x13 and x14 are both 2.

In one aspect, provided is a compound of formula (X-6):

or a pharmaceutically acceptable salt thereof;

-   -   wherein:    -   R⁷⁰ and R⁷¹ are, independently of each other and independently        at each occurrence, halogen;    -   x15 and x16 are, independently of each other, 0, 1, 2, 3, 4, or        5;    -   n4 is 1 or 2;    -   T² is O or NH; and    -   A⁸ is a 5-12 membered heteroaryl.

In some embodiments of the compounds of formula (X-6), n4 is 1.

In some embodiments of the compounds of formula (X-6), n4 is 2.

In some embodiments of the compounds of formula (X-6), T² is O.

In some embodiments of the compounds of formula (X-6), T² is NH.

In some embodiments of the compounds of formula (X-5), R⁷⁹ and R⁷¹ are,independently of each other and independently at each occurrence,selected from fluoro and chloro.

In some embodiments of the compounds of formula (X-5), x15 and x16 areboth 1. In some embodiments, x15 is 1 and x16 is 2. In some embodiments,x15 is 2 and x16 is 1. In some embodiments, x15 and x16 are both 2.

In one aspect, provided is a compound of formula (X-7):

or a pharmaceutically acceptable salt thereof;

-   -   wherein:    -   R⁷² and R⁷³ are, independently of each other and independently        at each occurrence, halogen;    -   x17 and x18 are, independently of each other, 0, 1, 2, 3, 4, or        5;    -   A⁹ is a 5-12 membered heteroaryl; and    -   A¹⁹ is a 5-12 membered heteroaryl;    -   provided that A⁹ and A¹⁹ are not both simultaneously a moiety        selected from group consisting of:

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (X-7), R⁷² and R⁷³ are,independently of each other and independently at each occurrence,selected from fluoro and chloro.

In some embodiments of the compounds of formula (X-7), x17 and x18 areboth 1. In some embodiments, x17 is 1 and x18 is 2. In some embodiments,x17 is 2 and x18 is 1. In some embodiments, x17 and x18 are both 2.

In one aspect, provided is a compound of formula (X-8):

or a pharmaceutically acceptable salt thereof;

-   -   wherein:    -   R⁷⁴ and R⁷⁵ are, independently of each other and independently        at each occurrence, halogen;    -   x19 and x20 are, independently of each other, 0, 1, 2, 3, 4, or        5;    -   A¹¹ is C₆-C₁₀ aryl or 5-12 membered heteroaryl;    -   Q⁶ is selected from the group consisting of:

-   -   wherein * represents the point of attachment to the

moiety, and # represents the point of attachment to the A¹¹-(R⁷⁵)_(x20)moiety;

-   -   T³ is O or NH;    -   T⁴ is O or NH;    -   R⁷⁶ is selected from hydrogen, —OH, and NH₂;    -   R⁷⁷ is selected from hydrogen, —OH, and NH₂;    -   R⁷⁸ is hydrogen or —OH; and    -   provided that one of (i) or (ii) applies:        -   (i) when A¹¹ is C₆-C₁₀ aryl, Q⁶ is selected from the group            consisting of:

-   -   (ii) when A¹¹ is 5-12 membered heteroaryl, Q⁶ is

In some embodiments of the compounds of formula (X-8), A¹¹ is C₆-C₁₀aryl, and Q⁶ is selected from the group consisting of:

In some embodiments of the compounds of formula (X-8), A¹¹ is C₆-C₁₀aryl, and Q⁶ is

In some embodiments, A¹¹ is phenyl.

In some embodiments of the compounds of formula (X-8), A¹¹ is C₆-C₁₀aryl, and Q⁶ is

In some embodiments, R⁷⁶ is hydrogen. In some embodiments, R⁷⁶ is —OH.In some embodiments, R⁷⁶ is —NH₂. In some embodiments, A¹¹ is phenyl.

In some embodiments of the compounds of formula (X-8), A¹¹ is C₆-C₁₀aryl, and Q⁶ is

In some embodiments, A¹¹ is phenyl.

In some embodiments of the compounds of formula (X-8), A¹¹ is C₆-C₁₀aryl, and Q⁶ is

In some embodiments, R⁷⁷ is hydrogen. In some embodiments, R⁷⁷ is —OH.In some embodiments, R⁷⁷ is NH₂. In some embodiments, A¹¹ is phenyl.

In some embodiments of the compounds of formula (X-8), A¹¹ is C₆-C₁₀aryl, and Q⁶ is

In some embodiments, A¹¹ is phenyl.

In some embodiments of the compounds of formula (X-8), A¹¹ is C₆-C₁₀aryl, and Q⁶ is

In some embodiments, T³ is O. In some embodiments, T³ is NH. In someembodiments, A¹¹ is phenyl.

In some embodiments of the compounds of formula (X-8), A¹¹ is C₆-C₁₀aryl, and Q⁶ is

In some embodiments, T⁴ is O. In some embodiments, T⁴ is NH. In someembodiments, A¹¹ is phenyl.

In some embodiments of the compounds of formula (X-8), A¹¹ is 5-12membered heteroaryl, and Q⁶ is

In some embodiments of the compounds of formula (X-8), A¹¹ is 5-12membered heteroaryl, and Q⁶ is

In some embodiments of the compounds of formula (X-8), A¹¹ is 5-12membered heteroaryl, and Q⁶ is

In some embodiments, R⁷⁸ is hydrogen. In some embodiments, R⁷⁸ is —OH.

In some embodiments of the compounds of formula (X-8), R⁷⁴ and R⁷⁵ are,independently of each other and independently at each occurrence,selected from fluoro and chloro.

In some embodiments of the compounds of formula (X-8), x19 and x20 areboth 1. In some embodiments, x19 is 1 and x20 is 2. In some embodiments,x19 is 2 and x20 is 1. In some embodiments, x19 and x20 are both 2.

In one aspect, provided is a compound of formula (X-9):

or a pharmaceutically acceptable salt thereof;

-   -   wherein:    -   R⁷⁹ and R⁸⁰ are, independently of each other and independently        at each occurrence, halogen;    -   x21 and x22 are, independently of each other, 0, 1, 2, 3, 4, or        5;    -   A¹² is C₆-C₁₀ aryl or 5-12 membered heteroaryl;    -   Q⁷ is selected from the group consisting of:

-   -   wherein * represents the point of attachment to the moiety, and        # represents the point of attachment to the A¹²-(R⁸⁰)_(x22)        moiety;    -   T⁵ is O or NH;    -   T⁶ is O or NH;    -   R⁸¹ is selected from hydrogen, —OH, and NH₂;    -   R⁸² is selected from hydrogen, —OH, and NH₂;    -   R⁸³ is hydrogen or —OH; and    -   provided that one of (i) or (ii) applies:        -   (i) when A¹² is C₆-C₁₀ aryl, Q⁷ is selected from the group            consisting of:

-   -   (ii) when A¹² is 5-12 membered heteroaryl, Q⁷ is

In some embodiments of the compounds of formula (X-9), A¹² is C₆-C₁₀aryl, and Q⁷ is selected from the group consisting of:

In some embodiments of the compounds of formula (X-9), A¹² is C₆-C₁₀aryl, and Q⁷ is

In some embodiments, R⁸¹ is hydrogen. In some embodiments, R⁸¹ isselected from —OH. In some embodiments, R⁸¹ is selected from —NH₂. Insome embodiments, A¹² is phenyl.

In some embodiments of the compounds of formula (X-9), A¹² is C₆-C₁₀aryl, and Q⁷ is

In some embodiments, R⁸² is hydrogen. In some embodiments, R⁸² isselected from —OH. In some embodiments, R⁸² is selected from —NH₂. Insome embodiments, A¹² is phenyl.

In some embodiments of the compounds of formula (X-9), A¹² is C₆-C₁₀aryl, and Q⁷ is

In some embodiments, A¹² is phenyl.

In some embodiments of the compounds of formula (X-9), A¹² is C₆-C₁₀aryl, and Q⁷ is

In some embodiments, T⁵ is O. In some embodiments, T⁵ is NH. In someembodiments, A¹² is phenyl.

In some embodiments of the compounds of formula (X-9), A¹² is C₆-C₁₀aryl, and Q⁷ is

In some embodiments, T⁶ is O. In some embodiments, T⁶ is NH. In someembodiments, A¹² is phenyl.

In some embodiments of the compounds of formula (X-9), A¹² is 5-12membered heteroaryl, and Q⁷ is

In some embodiments of the compounds of formula (X-9), A¹² is 5-12membered heteroaryl, and Q⁷ is

In some embodiments of the compounds of formula (X-9), A¹² is 5-12membered heteroaryl, and Q⁷ is

In some embodiments, R⁸³ is hydrogen. In some embodiments, R⁸³ is —OH.

In some embodiments of the compounds of formula (X-9), R⁷⁹ and R⁸⁰ are,independently of each other and independently at each occurrence,selected from fluoro and chloro.

In some embodiments of the compounds of formula (X-9), x21 and x22 areboth 1. In some embodiments, x21 is 1 and x22 is 2. In some embodiments,x21 is 2 and x22 is 1. In some embodiments, x21 and x22 are both 2.

In one aspect, provided is a compound of formula (XX):

or a pharmaceutically acceptable salt thereof;wherein:

-   -   X⁵ is CH or N;    -   Y⁵ is selected from the group consisting of a bond, NR^(Y5), and        O; provided that when X⁵ is N, then Y⁵ is a bond;    -   R^(Y5) is hydrogen or C₁-C₆ alkyl;    -   RN is hydrogen or C₁-C₆ alkyl;    -   m⁴, n⁵, p³, and q⁴, independently of each other, are 0 or 1;    -   r3 and s3, independently of each other, are 0, 1, or 2;    -   A¹³ is selected from the group consisting of:        -   C₆-C₁₀ aryl optionally substituted with one or more R⁹⁵            substituents; and        -   5-10 membered heteroaryl optionally substituted with one or            more R⁹⁵ substituents;    -   R⁹⁵ is selected, independently at each occurrence, from the        group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OH,        —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆ alkyl),        —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —NH(C₁-C₆        haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂,        —NR^(95-a)R^(95-b), —CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl),        —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),        —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆        haloalkyl)₂, —C(O)NR^(95-a)R^(95-b), —S(O)₂OH, —S(O)₂O(C₁-C₆        alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆        alkyl), —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,        —S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(95-a)R^(95-b), —OC(O)H,        —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H,        —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)C(O)H, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆        alkyl)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆        haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆        haloalkyl), —OS(O)₂(C₁-C₆ alkyl), —OS(O)₂(C₁-C₆ haloalkyl),        —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl),        —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆        haloalkyl)S(O)₂(C₁-C₆ haloalkyl);        -   wherein R^(95-a) and R^(95-b) are taken together with the            nitrogen atom which bears them to form a 3-10 membered            heterocycle;    -   R^(84a) and R^(84b) are independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, and halogen;    -   R^(85a) and R^(85b) are independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, and halogen;    -   when present, R^(86a) and R^(86b) are independently at each        occurrence selected from the group consisting of hydrogen, C₁-C₆        alkyl, and halogen;    -   when present, R^(87a) and R^(87b) are independently at each        occurrence selected from the group consisting of hydrogen, C₁-C₆        alkyl, and halogen;    -   or, R^(84a) and R^(85a) are taken together to form a C₁-C₆        alkylene moiety;    -   or, R^(84a) and an R^(86a) moiety, when present, are taken        together to form a C₁-C₆ alkylene moiety;    -   or, an R^(86a) moiety, when present, and an R^(87a) moiety, when        present, are taken together to form a C₁-C₆ alkylene moiety;    -   R⁸⁸ is selected from the group consisting of hydrogen, C₁-C₆        alkyl, C₁-C₆ haloalkyl, —C(O)(C₁-C₆ alkyl), —C(O)(C₁-C₆        haloalkyl), —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆        haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆        haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆ haloalkyl)₂,        —C(O)NR^(88-a)R^(88-b), —S(O)₂OH, —S(O)₂O(C₁-C₆ alkyl),        —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl),        —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆        haloalkyl)₂, and —S(O)₂NR^(88-a)R^(88-b);        -   wherein R^(88-a) and R^(88-b) are taken together with the            nitrogen atom which bears them to form a 3-10 membered            heterocycle;    -   R⁸⁹ is selected, independently at each occurrence, from the        group consisting of hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆        haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH,        —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl),        —NH(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂,        —NR^(89-a)R^(89-b), —CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl),        —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),        —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆        haloalkyl)₂, —C(C)NR^(89-a)R^(89-b), —S(O)₂OH, —S(O)₂O(C₁-C₆        alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆        alkyl), —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,        —S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(89-a)R^(89-b), —OC(O)H,        —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H,        —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)C(O)H, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆        alkyl)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆        haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆        haloalkyl), —OS(O)₂(C₁-C₆ alkyl), —OS(O)₂(C₁-C₆ haloalkyl),        —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl),        —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆        haloalkyl)S(O)₂(C₁-C₆ haloalkyl);    -   wherein R^(89-a) and R^(89-b) are taken together with the        nitrogen atom which bears them to form a 3-10 membered        heterocycle;    -   when present, R^(90a) and R^(90b) are taken together to form an        oxo (═O) substituent or an imido (═NH) substituent, or        alternatively, R^(90a) and R^(90b) are both hydrogen;    -   when present, R^(91a) is selected from the group consisting of        hydrogen, —OR^(91a-a), and NR^(91a-b)R^(91a-c)    -   when present, R^(91b) is hydrogen;    -   or alternatively, R^(91a) and R^(91b) are taken together to form        a moiety selected from the group consisting of —O—CH₂—CH₂—,        —CH₂—O—CH₂—, —CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—, —CH₂—O—CH₂—CH₂—,        —CH₂—CH₂—O—CH₂—, —CH₂—CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—CH₂—,        —CH₂—O—CH₂—CH₂—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—CH₂—CH₂—O—CH₂—,        and —CH₂—CH₂—CH₂—CH₂—O—;    -   when present, R^(92a) and R^(92b) are both hydrogen;    -   when present, R^(93a) and R^(93b) are taken together to form an        oxo (═O) substituent, or alternatively, R^(93a) and R^(93b) are        both hydrogen;    -   R^(91a-a) is selected from the group consisting of hydrogen,        C₁-C₆ alkyl, and C₁-C₆ haloalkyl;    -   or R^(91a-a) and R^(Y5) may be taken together to form a carbonyl        (C═O) moiety; and    -   R^(91a-b) and R^(91a-c), independently of each other, are        selected from the group consisting of hydrogen, C₁-C₆ alkyl, and        C₁-C₆ haloalkyl;    -   provided that when m⁴ is 0, n⁵ is 0, and q⁴ is 0, then A¹³ is a        substituent of formula (A¹³-a)

-   -   -   wherein            -   * represents the attachment point to the remainder of                the molecule;            -   Z¹⁴ is selected from the group consisting of                CR^(Z14-1)R^(Z14-2), NR^(Z14-2),                C(R^(Z14-1)R^(Z14-2))N(R^(Z14-2)), O,                C(R^(Z14-1)R^(Z14-2))O, s, C(R^(Z14-1)R^(Z14-2))S, and                —CR^(Z14-1)═CR^(Z14-1)—;                -   wherein R^(Z14-1) is hydrogen or R¹⁶; and R^(Z14-2)                    is hydrogen or R⁹⁵; Z¹⁵ is selected from the group                    consisting of CR^(Z15-1)R^(Z15-2), NR^(Z15-2),                    C(R^(Z15-1)R^(Z15-2))N(R^(Z15-2)), O,                    C(R^(Z15-1)R^(Z15-2))O, S, C(R^(Z15-1)R^(Z15-2))S,                    and —CR^(Z15-1)═CR^(Z15-1)—;                -   wherein R^(Z15-1) is hydrogen or R⁹⁵; and R^(Z15-2)                    is hydrogen or R⁹⁵; Z¹⁶, independently at each                    occurrence, is CH, CR⁹⁵, or N;            -   R⁹⁴ is hydrogen or R⁹⁵, or R⁹⁴ and R^(Z14-2) are taken                together to form a double bond between the carbon atom                bearing R⁹⁴ and Z¹⁴, or R⁹⁴ and R^(Z15-2) are taken                together to form a double bond between the carbon atom                bearing R⁹⁴ and Z¹⁵; and            -   x23 is 0, 1, 2, 3, or 4.

In some embodiments of the compounds of formula (XX):

-   -   X⁵ is CH or N;    -   Y⁵ is selected from the group consisting of a bond, NR^(Y5), and        O; provided that when X⁵ is N, then Y⁵ is a bond;    -   R^(Y5) is hydrogen or C₁-C₆ alkyl;    -   R^(N) is hydrogen or C₁-C₆ alkyl;    -   m⁴, n⁵, p³, and q⁴, independently of each other, are 0 or 1;    -   r3 and s3, independently of each other, are 0, 1, or 2;    -   A¹³ is selected from the group consisting of:        -   C₆-C₁₀ aryl optionally substituted with one or more R⁹⁵            substituents; and        -   5-10 membered heteroaryl optionally substituted with one or            more R⁹⁵ substituents;    -   R⁹⁵ is selected, independently at each occurrence, from the        group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OH,        —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆ alkyl),        —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —NH(C₁-C₆        haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂,        —NR^(95-a)R^(95-b), —CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl),        —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),        —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆        haloalkyl)₂, —C(O)NR^(95-a)R^(95-b), —S(O)₂OH, —S(O)₂O(C₁-C₆        alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆        alkyl), —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,        —S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(95-a)R^(95-b), —OC(O)H,        —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H,        —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)C(O)H, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆        alkyl)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆        haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆        haloalkyl), —OS(O)₂(C₁-C₆ alkyl), —OS(O)₂(C₁-C₆ haloalkyl),        —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl),        —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆        haloalkyl)S(O)₂(C₁-C₆ haloalkyl);        -   wherein R^(95-a) and R^(95-b) are taken together with the            nitrogen atom which bears them to form a 3-10 membered            heterocycle;    -   R^(84a) and R^(84b) are independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, and halogen;    -   R^(85a) and R^(85b) are independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, and halogen;    -   when present, R^(86a) and R^(86b) are independently at each        occurrence selected from the group consisting of hydrogen, C₁-C₆        alkyl, and halogen;    -   when present, R^(87a) and R^(87b) are independently at each        occurrence selected from the group consisting of hydrogen, C₁-C₆        alkyl, and halogen;    -   or, R^(84a) and R^(85a) are taken together to form a C₁-C₆        alkylene moiety;    -   or, R^(84a) and an R^(86a) moiety, when present, are taken        together to form a C₁-C₆ alkylene moiety;    -   or, an R^(86a) moiety, when present, and an R^(87a) moiety, when        present, are taken together to form a C₁-C₆ alkylene moiety;    -   R⁸⁸ is selected from the group consisting of hydrogen, C₁-C₆        alkyl, C₁-C₆ haloalkyl, —C(O)(C₁-C₆ alkyl), —C(O)(C₁-C₆        haloalkyl), —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆        haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆        haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆ haloalkyl)₂,        —C(O)NR^(88-a)R^(88-b), —S(O)₂OH, —S(O)₂O(C₁-C₆ alkyl),        —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl),        —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆        haloalkyl)₂, and —S(O)₂NR^(88-a)R^(88-b);        -   wherein R^(88-a) and R^(88-b) are taken together with the            nitrogen atom which bears them to form a 3-10 membered            heterocycle;    -   R⁸⁹ is selected, independently at each occurrence, from the        group consisting of hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆        haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH,        —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl),        —NH(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂,        —NR^(89-a)R^(89-b), —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆        haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆        haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆ haloalkyl)₂,        —C(O)NR^(89-a)R^(89-b), —S(O)₂OH, —S(O)₂O(C₁-C₆ alkyl),        —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl),        —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆        haloalkyl)₂, —S(O)₂NR^(89-a)R^(89-b), —OC(O)H, —OC(O)(C₁-C₆        alkyl), —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H, —N(H)C(O)(C₁-C₆        alkyl), —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)C(O)H,        —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆        haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆        haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆        haloalkyl), —OS(O)₂(C₁-C₆ alkyl), —OS(O)₂(C₁-C₆ haloalkyl),        —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl),        —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆        haloalkyl)S(O)₂(C₁-C₆ haloalkyl);    -   wherein R^(89-a) and R^(89-b) are taken together with the        nitrogen atom which bears them to form a 3-10 membered        heterocycle;    -   when present, R^(90a) and R^(90b) are taken together to form an        oxo (═O) substituent or an imido (═NH) substituent, or        alternatively, R^(90a) and R^(90b) are both hydrogen;    -   when present, R^(91a) is selected from the group consisting of        hydrogen, —OR^(91a-a), and NR^(91a-b)R^(91a-c);    -   when present, R^(91b) is hydrogen;    -   or alternatively, R^(91a) and R^(91b) are taken together to form        a moiety selected from the group consisting of —O—CH₂—CH₂—,        —CH₂—O—CH₂—, —CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—, —CH₂—O—CH₂—CH₂—,        —CH₂—CH₂—O—CH₂—, —CH₂—CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—CH₂—,        —CH₂—O—CH₂—CH₂—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—CH₂—CH₂—O—CH₂—,        and —CH₂—CH₂—CH₂—CH₂—O—;    -   when present, R^(92a) and R^(92b) are both hydrogen;    -   when present, R^(93a) and R^(93b) are taken together to form an        oxo (═O) substituent, or alternatively, R^(93a) and R^(93b) are        both hydrogen;    -   R^(91a-a) is selected from the group consisting of hydrogen,        C₁-C₆ alkyl, and C₁-C₆ haloalkyl;    -   or R^(91a-a) and R^(Y5) may be taken together to form a carbonyl        (C═O) moiety; and    -   R^(91a-b) and R^(91a-c), independently of each other, are        selected from the group consisting of hydrogen, C₁-C₆ alkyl, and        C₁-C₆ haloalkyl;    -   provided that when m⁴ is 0, n⁵ is 0, and q⁴ is 0, then p³ is 1        and A¹³ is a substituent of formula (A¹³-a)

-   -   -   wherein            -   * represents the attachment point to the remainder of                the molecule;            -   Z¹⁴ is selected from the group consisting of                CR^(Z14-1)R^(Z14-2), NR^(Z14-2),                C(R^(Z14-1)R^(Z14-2))N(R^(Z14-2)), O,                C(R^(Z14-1)R^(Z14-2))O, s, C(R^(Z14-1)R^(Z14-2))S, and                —CR^(Z14-1)═CR^(Z14-1)—;                -   wherein R^(Z14-1) is hydrogen or R¹⁶; and R^(Z14-2)                    is hydrogen or R⁹⁵; Z¹⁵ is selected from the group                    consisting of CR^(Z15-1)R^(Z15-2), NR^(Z15-2),                    C(R^(Z15-1)R^(Z15-2))N(R^(Z15-2)), O,                    C(R^(Z15-1)R^(Z15-2))O, s, C(R^(Z15-1)R^(Z15-2))S,                    and —CR^(Z15-1)═CR^(Z15-1)—;                -   wherein R^(Z15-1) is hydrogen or R⁹⁵; and R^(Z15-2)                    is hydrogen or R⁹⁵; Z¹⁶, independently at each                    occurrence, is CH, CR⁹⁵, or N;            -   R⁹⁴ is hydrogen or R⁹⁵, or R⁹⁴ and R^(Z14-2) are taken                together to form a double bond between the carbon atom                bearing R⁹⁴ and Z¹⁴, or R⁹⁴ and R^(Z15-2) are taken                together to form a double bond between the carbon atom                bearing R⁹⁴ and Z¹⁵; and            -   x23 is 0, 1, 2, 3, or 4.

In some embodiments, the compound of formula (XX) is a compound offormula (XX-I):

or a pharmaceutically acceptable salt thereof;wherein R^(N), R^(Y5), m⁴, n⁵, p³, q⁴, r3, s3, A¹³, R^(84a), R^(84b),R^(85a), R^(85b), R^(86a), R^(86b), R^(87a), R^(87b), R⁸⁸, R⁸⁹, R^(90a),R^(90b), R^(91a), R^(91b), R^(92a), R^(92b), R^(93a), and R^(93b) are asdefined for the compounds of formula (XX).

In some embodiments, the compound of formula (XX) is a compound offormula (XX-II):

or a pharmaceutically acceptable salt thereof;wherein R^(N), m⁴, n⁵, p³, q⁴, r3, s3, A¹³, R^(84a), R^(84b), R^(85a),R^(85b), R^(86a), R^(86b), R^(87a), R^(87b), R⁸⁸, R⁸⁹, R^(90a), R^(90b),R^(91a), R^(91b), R^(92a), R^(92b), R^(93a), and R^(93b) are as definedfor the compounds of formula (XX).

In some embodiments of the compounds of formulae (XX), (XX-I), and(XX-II), the moiety

wherein # represents the attachment point to the remainder of themolecule, is

wherein # represents the attachment point to the remainder of themolecule.

In some embodiments, the compound of formula (XX) or the compound offormula (XX-I) is a compound of formula (XX-I-1):

or a pharmaceutically acceptable salt thereof;

-   -   wherein R^(N), R^(Y5), R⁸⁸, R⁸⁹, R^(93a), and R^(93b) are as        defined in the compounds of formula (XX), and wherein A¹³ is a        substituent of formula (A¹³-a)

-   -   -   wherein            -   * represents the attachment point to the remainder of                the molecule;            -   Z¹⁴ is selected from the group consisting of                CR^(Z14-1)R^(Z14-2), NR^(Z14-2),                C(R^(Z14-1)R^(Z14-2))N(R^(Z14-2)), O,                C(R^(Z14-1)R^(Z14-2))O, s, C(R^(Z14-1)R^(Z14-2))S, and                —CR^(Z14-1)═CR^(Z14-1)—;                -   wherein R^(Z14-1) is hydrogen or R¹⁶; and R^(Z14-2)                    is hydrogen or R⁹⁵; Z¹⁵ is selected from the group                    consisting of CR^(Z15-1)R^(Z15-2), NR^(Z15-2),                    C(R^(Z15-1)R^(Z15-2))N(R^(Z15-2)), O,                    C(R^(Z15-1)R^(Z15-2))O, S, C(R^(Z15-1)R^(Z15-2))S,                    and —CR^(Z15-1)═CR^(Z15-1)—,                -   wherein R^(Z15-1) is hydrogen or R⁹⁵; and R^(Z15-2)                    is hydrogen or R⁹⁵; Z¹⁶, independently at each                    occurrence, is CH, CR⁹⁵, or N;            -   R⁹⁴ is hydrogen or R⁹⁵, or R⁹⁴ and R^(Z14-2) are taken                together to form a double bond between the carbon atom                bearing R⁹⁴ and Z¹⁴, or R⁹⁴ and R^(Z15-2) are taken                together to form a double bond between the carbon atom                bearing R⁹⁴ and Z¹⁵;            -   x23 is 0, 1, 2, 3, or 4; and            -   R⁹⁵ is selected, independently at each occurrence, from                the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆                haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl),                —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,                —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆                alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(95-a)R^(95-b), —CN,                —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),                —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆                haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆                haloalkyl)₂, —C(O)NR^(95-a)R^(95-b), —S(O)₂OH,                —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),                —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆                haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆                haloalkyl)₂, —S(O)₂NR^(95-a)R^(95-b), —OC(O)H,                —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl).

In some embodiments of the compounds of formula (XX-I-1), R^(N) ishydrogen or C₁-C₆ alkyl. In some embodiments of the compounds of formula(XX-I-1), R^(N) is hydrogen.

In some embodiments of the compounds of formula (XX-I-1), R^(Y5) ishydrogen or C₁-C₆ alkyl. In some embodiments of the compounds of formula(XX-I-1), R^(Y5) is hydrogen.

In some embodiments of the compounds of formula (XX-I-1), R⁸⁸ ishydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In some embodiments, R⁸⁸ ishydrogen.

In some embodiments of the compounds of formula (XX-I-1), R⁸⁹ isselected, independently at each occurrence, from the group consisting ofhydrogen, halogen, C₁-C₆ alkyl, and C₁-C₆ haloalkyl. In some embodimentsof the compounds of formula (XX-I-1), R⁸⁹ is, independently at eachoccurrence, hydrogen or halogen. In some embodiments, R⁸⁹ is,independently at each occurrence, hydrogen, fluoro or chloro. In someembodiments, one R⁸⁹ is chloro and the remaining R⁸⁹ substituents arehydrogen.

In some embodiments of the compounds of formula (XX-I-1), R^(93a) andR^(93b) are taken together to form an oxo (═O) substituent. In someembodiments of the compounds of formula (XX-I-1), R^(93a) and R^(93b)are both hydrogen.

In some embodiments of the compounds of formula (XX-I-1), (A¹³-a) isselected from the group consisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A¹³-a) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A¹³-a) is selected from the groupconsisting of:

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A¹³-a) is

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, (A¹³-a) is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (XX-I-1), the moiety

wherein # represents the attachment point to the remainder of themolecule, is

wherein # represents the attachment point to the remainder of themolecule.

In some embodiments, the compound of formula (XX) or the compound offormula (XX-I) is a compound of formula (XX-I-2):

or a pharmaceutically acceptable salt thereof;wherein R^(N), R^(Y5), A¹³, R⁸⁸, and R⁸⁹ are as defined in the compoundsof formula (XX).

In some embodiments of the compounds of formula (XX-I-2), R^(N) ishydrogen or C₁-C₆ alkyl. In some embodiments of the compounds of formula(XX-I-2), R^(N) is hydrogen.

In some embodiments of the compounds of formula (XX-I-2), R^(Y5) ishydrogen or C₁-C₆ alkyl. In some embodiments of the compounds of formula(XX-I-2), R^(Y5) is hydrogen.

In some embodiments of the compounds of formula (XX-I-2), R⁸⁸ ishydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In some embodiments, R⁸⁸ ishydrogen.

In some embodiments of the compounds of formula (XX-I-2), R⁸⁹ isselected, independently at each occurrence, from the group consisting ofhydrogen, halogen, C₁-C₆ alkyl, and C₁-C₆ haloalkyl. In some embodimentsof the compounds of formula (XX-I-2), R⁸⁹ is, independently at eachoccurrence, hydrogen or halogen. In some embodiments, R⁸⁹ is,independently at each occurrence, hydrogen, fluoro or chloro. In someembodiments, one R⁸⁹ is chloro and the remaining R⁸⁹ substituents arehydrogen.

In some embodiments of the compounds of formula (XX-I-2), A¹³ isselected from the group consisting of C₆-C₁₄ aryl optionally substitutedwith one or more R⁹⁵ substituents; and 5-14 membered heteroaryloptionally substituted with one or more R⁹⁵ substituents. In someembodiments, A¹³ is C₆-C₁₄ aryl optionally substituted with one or moreR⁹⁵ substituents. In some embodiments, A¹³ is C₆-C₁₀ aryl optionallysubstituted with one or more R⁹⁵ substituents.

In some embodiments, A¹³ is selected from the group consisting of

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is phenyl optionally substituted withone or more R⁹⁵ substituents. In some embodiments, A¹³ is selected fromthe group consisting of

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is naphthyl optionally substitutedwith one or more R⁹⁵ substituents. In some embodiments, A¹³ is selectedfrom the group consisting of

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (XX-I-2), A¹³ is 5-14membered heteroaryl optionally substituted with one or more R⁹⁵substituents. In some embodiments, A¹³ is 5-10 membered heteroaryloptionally substituted with one or more R⁹⁵ substituents. In someembodiments, A¹³ is selected from the group consisting of

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is pyridyl optionally substitutedwith one or more R⁹⁵ substituents. In some embodiments, A¹³ is

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is quinolinyl optionally substitutedwith one or more A¹³ substituents. In some embodiments, A¹³ is selectedfrom the group consisting of

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is and

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (XX-I-2), the moiety

wherein # represents the attachment point to the remainder of themolecule, is

wherein # represents the attachment point to the remainder of themolecule.

In some embodiments, the compound of formula (XX) or the compound offormula (XX-I) is a compound of formula (XX-I-2b):

or a pharmaceutically acceptable salt thereof;wherein R^(N), R^(Y5), A¹³, R⁸⁸, and R⁸⁹ are as defined in the compoundsof formula (XX).

In some embodiments of the compounds of formula (XX-I-2b), R^(N) ishydrogen or C₁-C₆ alkyl. In some embodiments of the compounds of formula(XX-I-2b), R^(N) is hydrogen.

In some embodiments of the compounds of formula (XX-I-2b), R^(Y5) ishydrogen or C₁-C₆ alkyl. In some embodiments of the compounds of formula(XX-I-2b), R^(Y5) is hydrogen.

In some embodiments of the compounds of formula (XX-I-2b), R⁸⁸ ishydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In some embodiments, R⁸⁸ ishydrogen.

In some embodiments of the compounds of formula (XX-I-2b), R⁸⁹ isselected, independently at each occurrence, from the group consisting ofhydrogen, halogen, C₁-C₆ alkyl, and C₁-C₆ haloalkyl. In some embodimentsof the compounds of formula (XX-I-2b), R⁸⁹ is, independently at eachoccurrence, hydrogen or halogen. In some embodiments, R⁸⁹ is,independently at each occurrence, hydrogen, fluoro or chloro. In someembodiments, one R⁸⁹ is chloro and the remaining R⁸⁹ substituents arehydrogen.

In some embodiments of the compounds of formula (XX-I-2b), A¹³ isselected from the group consisting of C₆-C₁₄ aryl optionally substitutedwith one or more R⁹⁵ substituents; and 5-14 membered heteroaryloptionally substituted with one or more R⁹⁵ substituents. In someembodiments, A¹³ is C₆-C₁₄ aryl optionally substituted with one or moreR⁹⁵ substituents. In some embodiments, A¹³ is C₆-C₁₀ aryl optionallysubstituted with one or more R⁹⁵ substituents. In some embodiments, A¹³is selected from the group consisting of

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is phenyl optionally substituted withone or more R⁹⁵ substituents. In some embodiments, A¹³ is selected fromthe group consisting of

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is naphthyl optionally substitutedwith one or more R⁹⁵ substituents. In some embodiments, A¹³ is selectedfrom the group consisting of

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (XX-I-2b), A¹³ is 5-14membered heteroaryl optionally substituted with one or more R⁹⁵substituents. In some embodiments, A¹³ is 5-10 membered heteroaryloptionally substituted with one or more R⁹⁵ substituents. In someembodiments, A¹³ is selected from the group consisting of

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is pyridyl optionally substitutedwith one or more R⁹⁵ substituents. In some embodiments, A¹³ is

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is quinolinyl optionally substitutedwith one or more A¹³ substituents. In some embodiments, A¹³ is selectedfrom the group consisting of

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is and

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (XX-I-2b), the moiety

wherein # represents the attachment point to the remainder of themolecule, is

wherein # represents the attachment point to the remainder of themolecule.

In some embodiments, the compound of formula (XX) or the compound offormula (XX-I) is a compound of formula (XX-I-3):

or a pharmaceutically acceptable salt thereof;

-   -   wherein R^(N), R^(Y5), A¹³, R⁸⁸, and R⁸⁹ are as defined in the        compounds of formula (XX);    -   R^(91a) is selected from the group consisting of hydrogen,        —OR^(91a-a) and NR^(91a-b)R^(91a-c);    -   R^(91a-a) is selected from the group consisting of hydrogen,        C₁-C₆ alkyl, and C₁-C₆ haloalkyl;    -   or R^(91a-a) and R^(Y5) may be taken together to form a carbonyl        (C═O) moiety; and    -   R^(91a-b) and R^(91a-c), independently of each other, are        selected from the group consisting of hydrogen, C₁-C₆ alkyl, and        C₁-C₆ haloalkyl.

In some embodiments of the compounds of formula (XX-I-3), R^(N) ishydrogen or C₁-C₆ alkyl. In some embodiments of the compounds of formula(XX-I-3), R^(N) is hydrogen.

In some embodiments of the compounds of formula (XX-I-3), R^(Y5) ishydrogen or C₁-C₆ alkyl. In some embodiments of the compounds of formula(XX-I-3), R^(Y5) is hydrogen.

In some embodiments of the compounds of formula (XX-I-3), R⁸⁸ ishydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In some embodiments, R⁸⁸ ishydrogen.

In some embodiments of the compounds of formula (XX-I-3), R⁸⁹ isselected, independently at each occurrence, from the group consisting ofhydrogen, halogen, C₁-C₆ alkyl, and C₁-C₆ haloalkyl. In some embodimentsof the compounds of formula (XX-I-3), R⁸⁹ is, independently at eachoccurrence, hydrogen or halogen. In some embodiments, R⁸⁹ is,independently at each occurrence, hydrogen, fluoro or chloro. In someembodiments, one R⁸⁹ is chloro and the remaining R⁸⁹ substituents arehydrogen.

In some embodiments of the compounds of formula (XX-I-3), R^(91a) ishydrogen or —OR^(91a-a) In some embodiments, R^(91a) is hydrogen. Insome embodiments, R^(91a) is —COR^(91a-a), wherein R^(91a-a) is selectedfrom the group consisting of hydrogen, C₁-C₆ alkyl, and C₁-C₆ haloalkyl;or R^(91a-a) and R^(Y5) may be taken together to form a carbonyl (C═O)moiety. In some embodiments, R^(91a) is —OR^(91a-a) wherein R^(91a-a) ishydrogen.

In some embodiments of the compounds of formula (XX-I-3), A¹³ isselected from the group consisting of C₆-C₁₄ aryl optionally substitutedwith one or more R⁹⁵ substituents; and 5-14 membered heteroaryloptionally substituted with one or more R⁹⁵ substituents. In someembodiments, A¹³ is C₆-C₁₄ aryl optionally substituted with one or moreR⁹⁵ substituents. In some embodiments, A¹³ is C₆-C₁₀ aryl optionallysubstituted with one or more R⁹⁵ substituents.

In some embodiments, A¹³ is selected from the group consisting of

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is phenyl optionally substituted withone or more R⁹⁵ substituents. In some embodiments, A¹³ is selected fromthe group consisting of

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is naphthyl optionally substitutedwith one or more R⁹⁵ substituents. In some embodiments, A¹³ is selectedfrom the group consisting of

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (XX-I-3), A¹³ is 5-14membered heteroaryl optionally substituted with one or more R⁹⁵substituents. In some embodiments, A¹³ is 5-10 membered heteroaryloptionally substituted with one or more R⁹⁵ substituents. In someembodiments, A¹³ is selected from the group consisting of

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is pyridyl optionally substitutedwith one or more R⁹⁵ substituents. In some embodiments, A¹³ is

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is quinolinyl optionally substitutedwith one or more A¹³ substituents. In some embodiments, A¹³ is selectedfrom the group consisting of

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is and

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (XX-I-3), the moiety

wherein # represents the attachment point to the remainder of themolecule, is

wherein # represents the attachment point to the remainder of themolecule.

In some embodiments, the compound of formula (XX) or the compound offormula (XX-I) is a compound of formula (XX-II-3):

or a pharmaceutically acceptable salt thereof;

-   -   wherein R^(N), R^(Y5), A¹³, R⁸⁸, and R⁸⁹ are as defined in the        compounds of formula (XX);    -   R^(91a) is selected from the group consisting of hydrogen,        —OR^(91a-a) and NR^(91a-b)R^(91a-c);    -   R^(91a-a) is selected from the group consisting of hydrogen,        C₁-C₆ alkyl, and C₁-C₆ haloalkyl;    -   or R^(91a-a) and R^(Y5) may be taken together to form a carbonyl        (C═O) moiety; and    -   R^(91a-b) and R^(91a-c), independently of each other, are        selected from the group consisting of hydrogen, C₁-C₆ alkyl, and        C₁-C₆ haloalkyl.

In some embodiments of the compounds of formula (XX-II-3), R^(N) ishydrogen or C₁-C₆ alkyl. In some embodiments of the compounds of formula(XX-II-3), R^(N) is hydrogen.

In some embodiments of the compounds of formula (XX-II-3), R⁸⁸ ishydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In some embodiments, R⁸⁸ ishydrogen.

In some embodiments of the compounds of formula (XX-II-3), R⁸⁹ isselected, independently at each occurrence, from the group consisting ofhydrogen, halogen, C₁-C₆ alkyl, and C₁-C₆ haloalkyl. In some embodimentsof the compounds of formula (XX-II-3), R⁸⁹ is, independently at eachoccurrence, hydrogen or halogen. In some embodiments, R⁸⁹ is,independently at each occurrence, hydrogen, fluoro or chloro. In someembodiments, one R⁸⁹ is chloro and the remaining R⁸⁹ substituents arehydrogen.

In some embodiments of the compounds of formula (XX-II-3), R^(91a) ishydrogen or —OR^(91a-a) In some embodiments, R^(91a) is hydrogen. Insome embodiments, R^(91a) is —OR^(91a-a), wherein R^(91a-a) is selectedfrom the group consisting of hydrogen, C₁-C₆ alkyl, and C₁-C₆ haloalkyl;or R^(91a-a) and R^(Y5) may be taken together to form a carbonyl (C═O)moiety. In some embodiments, R^(91a) is —OR^(91a-a), wherein R^(91a-a)is hydrogen.

In some embodiments of the compounds of formula (XX-II-3), A¹³ isselected from the group consisting of C₆-C₁₄ aryl optionally substitutedwith one or more R⁹⁵ substituents; and 5-14 membered heteroaryloptionally substituted with one or more R⁹⁵ substituents. In someembodiments, A¹³ is C₆-C₁₄ aryl optionally substituted with one or moreR⁹⁵ substituents. In some embodiments, A¹³ is C₆-C₁₀ aryl optionallysubstituted with one or more R⁹⁵ substituents. In some embodiments, A¹³is selected from the group consisting of

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is phenyl optionally substituted withone or more R⁹⁵ substituents. In some embodiments, A¹³ is selected fromthe group consisting of

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is naphthyl optionally substitutedwith one or more R⁹⁵ substituents. In some embodiments, A¹³ is selectedfrom the group consisting of

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (XX-II-3), A¹³ is 5-14membered heteroaryl optionally substituted with one or more R⁹⁵substituents. In some embodiments, A¹³ is 5-10 membered heteroaryloptionally substituted with one or more R⁹⁵ substituents. In someembodiments, A¹³ is selected from the group consisting of

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is pyridyl optionally substitutedwith one or more R⁹⁵ substituents. In some embodiments, A¹³ is

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is quinolinyl optionally substitutedwith one or more A¹³ substituents. In some embodiments, A¹³ is selectedfrom the group consisting of

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is

wherein the * represents the attachment point to the remainder of themolecule. In some embodiments, A¹³ is and

wherein the * represents the attachment point to the remainder of themolecule.

In some embodiments of the compounds of formula (XX-II-3), the moiety

wherein # represents the attachment point to the remainder of themolecule, is

wherein # represents the attachment point to the remainder of themolecule.

In the descriptions herein, it is understood that every description,variation, embodiment or aspect of a moiety may be combined with everydescription, variation, embodiment or aspect of other moieties the sameas if each and every combination of descriptions is specifically andindividually listed. For example, every description, variation,embodiment or aspect provided herein with respect to X¹ of formula (I)may be combined with every description, variation, embodiment or aspectof m¹, m², n¹, n², p¹, p², q¹, q², r, s, X², Y¹, Y², A¹, A², R^(1a),R^(1b), R^(2a), R^(2b), R^(3a), R^(3b), R^(4a), R^(4b), R^(5a), R^(5b),R^(6a), R^(6b), R^(7a), R^(7b), R^(8a), R^(8b), R^(9a), R^(9b), R^(10a),R^(10b), R^(11a), R^(11b), R^(12a) and R^(12b) the same as if each andevery combination were specifically and individually listed. It is alsounderstood that all descriptions, variations, embodiments or aspects offormula (I), where applicable, apply equally to other formulae detailedherein, and are equally described, the same as if each and everydescription, variation, embodiment or aspect were separately andindividually listed for all formulae. For example, all descriptions,variations, embodiments or aspects of formula (I), where applicable,apply equally to any of formulae (1-1), (1-2), (1-3), (1-4), (2-2),(2-3), (2-4), (3-3), (3-4), and (4-4) detailed herein, and are equallydescribed, the same as if each and every description, variation,embodiment or aspect were separately and individually listed for allformulae. Similarly, every description, variation, embodiment or aspectprovided herein with respect to X³ of formula (II) may be combined withevery description, variation, embodiment or aspect of m³, n³, r², s²,X⁴, Y³, Y⁴, A³, A⁴, R^(17a), R^(17b), R^(18a), R^(18b), R^(19a),R^(19b), R^(20a), R^(20b), R^(21a), R^(21b), R^(22a), R^(22b), R^(23a),R^(23b), R^(24a), R^(24b), R^(25a), and R^(25b) the same as if each andevery combination were specifically and individually listed. It is alsounderstood that all descriptions, variations, embodiments or aspects offormula (II), where applicable, apply equally to other formulae detailedherein, and are equally described, the same as if each and everydescription, variation, embodiment or aspect were separately andindividually listed for all formulae. For example, all descriptions,variations, embodiments or aspects of formula (II) where applicable,apply equally to any of formulae (III), (IV), and (V) detailed herein,and are equally described, the same as if each and every description,variation, embodiment or aspect were separately and individually listedfor all formulae. Similarly, every description, variation, embodiment oraspect provided herein with respect to X⁵ of formula (XX) may becombined with every description, variation, embodiment or aspect ofR^(N), Y⁵, R^(Y5), m⁴, n⁵, p³, q⁴, r³, s³, A¹³, R^(84a), R^(84b),R^(85a), R^(85b), R^(86a), R^(86b), R^(87a), R^(87b), R⁸⁸, R⁸⁹, R^(90a),R^(90b), R^(91a), R^(91b), R^(92a), R^(92b), R^(93a), and R^(93b) thesame as if each and every combination were specifically and individuallylisted. It is also understood that all descriptions, variations,embodiments or aspects of formula (XX), where applicable, apply equallyto other formulae detailed herein, and are equally described, the sameas if each and every description, variation, embodiment or aspect wereseparately and individually listed for all formulae. For example, alldescriptions, variations, embodiments or aspects of formula (XX) whereapplicable, apply equally to any of formulae (XX-I), (XX-II), (XX-I-1),(XX-I-2), (XX-I-2b), (XX-I-3), and (XX-II-3) detailed herein, and areequally described, the same as if each and every description, variation,embodiment or aspect were separately and individually listed for allformulae.

Also provided are salts of compounds referred to herein, such aspharmaceutically acceptable salts. The present disclosure also includesany or all of the stereochemical forms, including any enantiomeric ordiastereomeric forms, and any tautomers or other forms of the compoundsdescribed. Thus, if a particular stereochemical form, such as a specificenantiomeric form or diastereomeric form, is depicted for a givencompound, then it is understood that any or all stereochemical forms,including any enantiomeric or diastereomeric forms, and any tautomers orother forms of any of that same compound are herein described andembraced by the invention.

A compound as detailed herein may in one aspect be in a purified formand compositions comprising a compound in purified forms are detailedherein. Compositions comprising a compound as detailed herein or a saltthereof are provided, such as compositions of substantially purecompounds. In some embodiments, a composition containing a compound asdetailed herein or a salt thereof is in substantially pure form. Unlessotherwise stated, “substantially pure” intends a composition thatcontains no more than 35% impurity, wherein the impurity denotes acompound other than the compound comprising the majority of thecomposition or a salt thereof. In some embodiments, a composition ofsubstantially pure compound or a salt thereof is provided wherein thecomposition contains no more than 25%, 20%, 15%, 10%, or 5% impurity. Insome embodiments, a composition of substantially pure compound or a saltthereof is provided wherein the composition contains or no more than 3%,2%, 1% or 0.5% impurity.

In some embodiments, provided is compound selected from compounds inTable 1, or a stereoisomer, tautomer, solvate, prodrug or salt thereof.Although certain compounds described in Table 1 are presented asspecific stereoisomers and/or in a non-stereochemical form, it isunderstood that any or all stereochemical forms, including anyenantiomeric or diastereomeric forms, and any tautomers or other formsof any of the compounds of Table 1 are herein described.

TABLE 1 Compound No. Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

Pharmaceutical Compositions and Formulations

Pharmaceutical compositions of any of the compounds detailed herein areembraced by this disclosure. Thus, the present disclosure includespharmaceutical compositions comprising a compound as detailed herein ora salt thereof and a pharmaceutically acceptable carrier or excipient.In one aspect, the pharmaceutically acceptable salt is an acid additionsalt, such as a salt formed with an inorganic or organic acid.Pharmaceutical compositions may take a form suitable for oral, buccal,parenteral, nasal, topical or rectal administration or a form suitablefor administration by inhalation.

A compound as detailed herein may in one aspect be in a purified formand compositions comprising a compound in purified forms are detailedherein. Compositions comprising a compound as detailed herein or a saltthereof are provided, such as compositions of substantially purecompounds. In some embodiments, a composition containing a compound asdetailed herein or a salt thereof is in substantially pure form.

In one variation, the compounds herein are synthetic compounds preparedfor administration to an individual. In another variation, compositionsare provided containing a compound in substantially pure form. Inanother variation, the present disclosure embraces pharmaceuticalcompositions comprising a compound detailed herein and apharmaceutically acceptable carrier. In another variation, methods ofadministering a compound are provided. The purified forms,pharmaceutical compositions and methods of administering the compoundsare suitable for any compound or form thereof detailed herein.

A compound detailed herein or salt thereof may be formulated for anyavailable delivery route, including an oral, mucosal (e.g., nasal,sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular,subcutaneous or intravenous), topical or transdermal delivery form. Acompound or salt thereof may be formulated with suitable carriers toprovide delivery forms that include, but are not limited to, tablets,caplets, capsules (such as hard gelatin capsules or soft elastic gelatincapsules), cachets, troches, lozenges, gums, dispersions, suppositories,ointments, cataplasms (poultices), pastes, powders, dressings, creams,solutions, patches, aerosols (e.g., nasal spray or inhalers), gels,suspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions or water-in-oil liquid emulsions), solutions andelixirs.

One or several compounds described herein or a salt thereof can be usedin the preparation of a formulation, such as a pharmaceuticalformulation, by combining the compound or compounds, or a salt thereof,as an active ingredient with a pharmaceutically acceptable carrier, suchas those mentioned above. Depending on the therapeutic form of thesystem (e.g., transdermal patch vs. oral tablet), the carrier may be invarious forms. In addition, pharmaceutical formulations may containpreservatives, solubilizers, stabilizers, re-wetting agents, emulgators,sweeteners, dyes, adjusters, and salts for the adjustment of osmoticpressure, buffers, coating agents or antioxidants. Formulationscomprising the compound may also contain other substances which havevaluable therapeutic properties. Pharmaceutical formulations may beprepared by known pharmaceutical methods. Suitable formulations can befound, e.g., in Remington's Pharmaceutical Sciences, Mack PublishingCompany, Philadelphia, Pa., 20th ed. (2000), which is incorporatedherein by reference.

Compounds as described herein may be administered to individuals in aform of generally accepted oral compositions, such as tablets, coatedtablets, and gel capsules in a hard or in soft shell, emulsions orsuspensions. Examples of carriers, which may be used for the preparationof such compositions, are lactose, corn starch or its derivatives, talc,stearate or its salts, etc. Acceptable carriers for gel capsules withsoft shell are, for instance, plant oils, wax, fats, semisolid andliquid poly-ols, and so on. In addition, pharmaceutical formulations maycontain preservatives, solubilizers, stabilizers, re-wetting agents,emulgators, sweeteners, dyes, adjusters, and salts for the adjustment ofosmotic pressure, buffers, coating agents or antioxidants.

Any of the compounds described herein can be formulated in a tablet inany dosage form described, for example, a compound as described hereinor a salt thereof can be formulated as a 10 mg tablet.

Compositions comprising a compound provided herein are also described.In one variation, the composition comprises a compound or salt thereofand a pharmaceutically acceptable carrier or excipient. In anothervariation, a composition of substantially pure compound is provided. Insome embodiments, the composition is for use as a human or veterinarymedicament. In some embodiments, the composition is for use in a methoddescribed herein. In some embodiments, the composition is for use in thetreatment of a disease or disorder described herein.

Methods of Use and Uses

Compounds and compositions detailed herein, such as a pharmaceuticalcomposition containing a compound of any formula provided herein or asalt thereof and a pharmaceutically acceptable carrier or excipient, maybe used in methods of administration and treatment as provided herein.The compounds and compositions may also be used in in vitro methods,such as in vitro methods of administering a compound or composition tocells for screening purposes and/or for conducting quality controlassays.

Provided herein is a method of treating a disease or disorder in anindividual in need thereof comprising administering a compound describesherein or any embodiment, variation, or aspect thereof, or apharmaceutically acceptable salt thereof. In some embodiments, thecompound, pharmaceutically acceptable salt thereof, or composition isadministered to the individual according to a dosage and/or method ofadministration described herein.

The compounds or salts thereof described herein and compositionsdescribed herein are believed to be effective for treating a variety ofdiseases and disorders. In some embodiments, a compound or salt thereofdescribed herein or a composition described herein may be used in amethod of treating a disease or disorder mediated by an integratedstress response (ISR) pathway. In some embodiments, the disease ordisorder is mediated by eukaryotic translation initiation factor 2α(eIF2a) or eukaryotic translation initiation factor 2B (eIF2B). In someembodiments, the disease or disorder is mediated by phosphorylation ofeIF2α and/or the guanine nucleotide exchange factor (GEF) activity ofeIF2B.

In some embodiments, a compound or salt thereof described herein or acomposition described herein may be used in a method of treating adisease or disorder, wherein the disease or disorder is aneurodegenerative disease, an inflammatory disease, an autoimmunedisease, a metabolic syndrome, a cancer, a vascular disease, amusculoskeletal disease (such as a myopathy), an ocular disease, or agenetic disorder.

In some embodiments, the disease or disorder is a neurodegenerativedisease. In some embodiments, the neurodegenerative disease is vanishingwhite matter disease, childhood ataxia with CNS hypomyelination,intellectual disability syndrome, Alzheimer's disease, prion disease,Creutzfeldt-Jakob disease, Parkinson's disease, amyotrophic lateralsclerosis (ALS) disease, Pelizaeus-Merzbacher disease, a cognitiveimpairment, a traumatic brain injury, a postoperative cognitivedysfunction (PCD), a neuro-otological syndrome, hearing loss,Huntington's disease, stroke, chronic traumatic encephalopathy, spinalcord injury, dementia, frontotemporal dementia (FTD), depression, or asocial behavior impairment. In some embodiments, the cognitiveimpairment is triggered by ageing, radiation, sepsis, seizure, heartattack, heart surgery, liver failure, hepatic encephalopathy,anesthesia, brain injury, brain surgery, ischemia, chemotherapy, cancertreatment, critical illness, concussion, fibromyalgia, or depression. Insome embodiments, the neurodegenerative disease is Alzheimer's disease.In some embodiments, the neurodegenerative disease is ageing-relatedcognitive impairment. In some embodiments, the neurodegenerative diseaseis a traumatic brain injury.

In some embodiments, a compound or salt thereof described herein or acomposition described herein may be used in a method of treatingAlzheimer's disease. In some embodiments, neurodegeneration, cognitiveimpairment, and/or amyloidogenesis is decreased.

In some embodiments, the disease or disorder is an inflammatory disease.In some embodiments, the inflammatory disease is arthritis, psoriaticarthritis, psoriasis, juvenile idiopathic arthritis, asthma, allergicasthma, bronchial asthma, tuberculosis, chronic airway disorder, cysticfibrosis, glomerulonephritis, membranous nephropathy, sarcoidosis,vasculitis, ichthyosis, transplant rejection, interstitial cystitis,atopic dermatitis, or inflammatory bowel disease. In some embodiments,the inflammatory bowel disease is Crohn' disease, ulcerative colitis, orceliac disease.

In some embodiments, the disease or disorder is an autoimmune disease.In some embodiments, the autoimmune disease is systemic lupuserythematosus, type 1 diabetes, multiple sclerosis, or rheumatoidarthritis.

In some embodiments, the disease or disorder is a metabolic syndrome. Insome embodiments, the metabolic syndrome is alcoholic liver steatosis,obesity, glucose intolerance, insulin resistance, hyperglycemia, fattyliver, dyslipidemia, hyperlipidemia, hyperhomocysteinemia, or type 2diabetes.

In some embodiments, the disease or disorder is a cancer. In someembodiments, the cancer is pancreatic cancer, breast cancer, kidneycancer, bladder cancer, prostate cancer, testicular cancer, urothelialcancer, endometrial cancer, ovarian cancer, cervical cancer, renalcancer, esophageal cancer, gastrointestinal stromal tumor (GIST),multiple myeloma, cancer of secretory cells, thyroid cancer,gastrointestinal carcinoma, chronic myeloid leukemia, hepatocellularcarcinoma, colon cancer, melanoma, malignant glioma, glioblastoma,glioblastoma multiforme, astrocytoma, dysplastic gangliocytoma of thecerebellum, Ewing's sarcoma, rhabdomyosarcoma, ependymoma,medulloblastoma, ductal adenocarcinoma, adenosquamous carcinoma,nephroblastoma, acinar cell carcinoma, neuroblastoma, or lung cancer. Insome embodiments, the cancer of secretory cells is non-Hodgkin'slymphoma, Burkitt's lymphoma, chronic lymphocytic leukemia, monoclonalgammopathy of undetermined significance (MGUS), plasmacytoma,lymphoplasmacytic lymphoma or acute lymphoblastic leukemia.

In some embodiments, the disease or disorder is a musculoskeletaldisease (such as a myopathy). In some embodiments, the musculoskeletaldisease is a myopathy, a muscular dystrophy, a muscular atrophy, amuscular wasting, or sarcopenia. In some embodiments, the musculardystrophy is Duchenne muscular dystrophy (DMD), Becker's disease,myotonic dystrophy, X-linked dilated cardiomyopathy, spinal muscularatrophy (SMA), or metaphyseal chondrodysplasia, Schmid type (MCDS). Insome embodiments, the myopathy is a skeletal muscle atrophy. In someembodiments, the musculoskeletal disease (such as the skeletal muscleatrophy) is triggered by ageing, chronic diseases, stroke, malnutrition,bedrest, orthopedic injury, bone fracture, cachexia, starvation, heartfailure, obstructive lung disease, renal failure, AcquiredImmunodeficiency Syndrome (AIDS), sepsis, an immune disorder, a cancer,ALS, a burn injury, denervation, diabetes, muscle disuse, limbimmobilization, mechanical unload, myositis, or a dystrophy.

In some embodiments, the disease or disorder is a genetic disorder, suchas Down syndrome or MEHMO syndrome (Mental retardation, Epilepticseizures, Hypogenitalism, Microcephaly, and Obesity).

In some embodiments, a compound or salt thereof described herein or acomposition described herein may be used in a method of treatingmusculoskeletal disease. In some embodiments, skeletal muscle mass,quality and/or strength are increased. In some embodiments, synthesis ofmuscle proteins is increased. In some embodiments, skeletal muscle fiberatrophy is inhibited.

In some embodiments, the disease or disorder is a vascular disease. Insome embodiments, the vascular disease is atherosclerosis, abdominalaortic aneurism, carotid artery disease, deep vein thrombosis, Buerger'sdisease, chronic venous hypertension, vascular calcification,telangiectasia or lymphoedema.

In some embodiments, the disease or disorder is an ocular disease. Insome embodiments, the ocular disease is glaucoma, age-related maculardegeneration, inflammatory retinal disease, retinal vascular disease,diabetic retinopathy, uveitis, rosacea, Sjogren's syndrome, orneovascularization in proliferative retinopathy.

In some embodiments, provided herein is a method of inhibiting an ISRpathway. The compounds or salts thereof described herein andcompositions described herein are believed to be effective forinhibiting an ISR pathway. In some embodiments, the method of inhibitingan ISR pathway comprises inhibiting the ISR pathway in a cell byadministering or delivering to the cell a compound described herein, ora pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition described herein. In some embodiments, the method ofinhibiting an ISR pathway comprises inhibiting the ISR pathway in anindividual by administering to the individual a compound describedherein, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition described herein. Inhibition of the ISRpathway can be determined by methods known in the art, such as westernblot, immunohistochemistry, or reporter cell line assays.

In some embodiments, the inhibition of the ISR pathway comprises bindingeIF2B. In some embodiments, the inhibition of the ISR pathway comprisesincreasing protein translation, increasing guanine nucleotide exchangefactor (GEF) activity of eIF2B, delaying or preventing apoptosis in acell, and/or inhibiting translation of one or more mRNAs comprising a 5′untranslated region (5′UTR) comprising at least one upstream openreading frame (uORF).

In some embodiments, provided herein are methods of increasing proteinproduction using a compound or salt described herein. The proteinproduction is increased relative to the same condition without thecompound or salt. Protein production can be increased either in vivo orin vitro. For example, protein production can be increased in vivo byadministering the compound or salt to an individual. In someembodiments, protein production is increased in vitro using the compoundor salt with a cell-free protein synthesis system (CFPS) or a cell-basedprotein expression system. The protein produced can be a heterologousprotein (e.g., a recombinant protein) or a native protein. Heterologousprotein production can be achieved using a recombinant nucleic acidencoding the protein. In some embodiments, the protein produced is anantibody or a fragment thereof. Other exemplary proteins can include,but are not limited to, enzymes, allergenic peptides or proteins (forexample, for use as a vaccine), recombinant protein, cytokines,peptides, hormones, erythropoietin (EPO), interferons,granulocyte-colony stimulating factor (G-CSF), anticoagulants, andclotting factors. The increase in protein production can be determinedby methods known in the art, such as western blot orimmunohistochemistry.

Cell-free protein synthesis (CFPS) systems are generally known, andinclude cellular machinery for protein expression in an in vitroenvironment. In some embodiments, the CFPS system includes a cellularextract (such as a eukaryotic cellular extract), which includes proteinexpression machinery. In some embodiment, the cellular machinery in theCFPS system comprises eukaryotic cellular machinery, such as eukaryoticinitiation factor 2 (eIF2) and/or eukaryotic initiation factor 2B(eIF2B), or one or more subunits thereof.

In some embodiments, there is a cell-free protein synthesis (CFPS)system comprising eukaryotic initiation factor 2 (eIF2) and a nucleicacid encoding a protein with a compound or salt as described herein. Insome embodiments, the protein is an antibody or a fragment thereof.Other exemplary proteins can include, but are not limited to, enzymes,allergenic peptides or proteins (for example, for use as a vaccine),recombinant protein, cytokines, peptides, hormones, erythropoietin(EPO), interferons, granulocyte-colony stimulating factor (G-CSF),anticoagulants, and clotting factors. In some embodiments, the CFPSsystem comprises a cell extract comprising the eIF2. In someembodiments, the CFPS system further comprises eIF2B.

In some embodiments, there is a method of producing a protein,comprising contacting a cell-free protein synthesis (CFPS) systemcomprising eukaryotic initiation factor 2 (eIF2) and a nucleic acidencoding a protein with a compound or salt thereof as described herein.In some embodiments, the protein is an antibody or a fragment thereof.Other exemplary proteins can include, but are not limited to, enzymes,allergenic peptides or proteins (for example, for use as a vaccine),recombinant protein, cytokines, peptides, hormones, erythropoietin(EPO), interferons, granulocyte-colony stimulating factor (G-CSF),anticoagulants, and clotting factors. In some embodiments, the CFPSsystem comprises a cell extract comprising the eIF2. In someembodiments, the CFPS system further comprises eIF2B. In someembodiments, the method comprises purifying the protein.

In some embodiments, there is a method of producing a protein,comprising contacting a eukaryotic cell comprising a nucleic acidencoding the protein with a compound or salt as described herein. Insome embodiments, the method comprises culturing the cell in an in vitroculture medium comprising the compound or salt. In some embodiments, thenucleic acid encoding the protein is a recombinant nucleic acid. In someembodiments, the eukaryotic cell is a human embryonic kidney (HEK) cellor a Chinese hamster ovary (CHO) cell. In other embodiments, theeukaryotic cell is a yeast cell (such as Saccharomyces cerevisiae orPichia pastoris), a wheat germ cell, an insect cell, a rabbitreticulocyte, a cervical cancer cell (such as a HeLa cell), a babyhamster kidney cell (such as BHK21 cells), a murine myeloma cell (suchas NSO or Sp2/0 cells), an HT-1080 cell, a PER.C6 cell, a plant cell, ahybridoma cell, or a human blood derived leukocyte. In some embodiments,the protein is an antibody or a fragment thereof. Other exemplaryproteins can include, but are not limited to, enzymes, allergenicpeptides or proteins (for example, for use as a vaccine), recombinantprotein, cytokines, peptides, hormones, erythropoietin (EPO),interferons, granulocyte-colony stimulating factor (G-CSF),anticoagulants, and clotting factors. In some embodiments, the methodcomprises purifying the protein.

In some embodiments, there is a method of culturing a eukaryotic cellcomprising a nucleic acid encoding a protein, comprising contacting theeukaryotic cell with an in vitro culture medium comprising a compound orsalt as described herein. In some embodiments, the nucleic acid encodingthe protein is a recombinant nucleic acid. In some embodiments, theeukaryotic cell is a human embryonic kidney (HEK) cell or a Chinesehamster ovary (CHO) cell. In other embodiments, the eukaryotic cell is ayeast cell (such as Saccharomyces cerevisiae or Pichia pastoris), awheat germ cell, an insect cell, a rabbit reticulocyte, a cervicalcancer cell (such as a HeLa cell), a baby hamster kidney cell (such asBHK21 cells), a murine myeloma cell (such as NSO or Sp2/0 cells), anHT-1080 cell, a PER.C6 cell, a plant cell, a hybridoma cell, or a humanblood derived leukocyte. In some embodiments, the protein is an antibodyor a fragment thereof. Other exemplary proteins can include, but are notlimited to, enzymes, allergenic peptides or proteins (for example, foruse as a vaccine), recombinant protein, cytokines, peptides, hormones,erythropoietin (EPO), interferons, granulocyte-colony stimulating factor(G-CSF), anticoagulants, and clotting factors. In some embodiments, themethod comprises purifying the protein.

In some embodiments, there is an in vitro cell culture medium,comprising the compound or salt described herein, and nutrients forcellular growth. In some embodiments, the culture medium comprises aeukaryotic cell comprising a nucleic acid encoding a protein. In someembodiments, the culture medium further comprises a compound forinducing protein expression. In some embodiments, the nucleic acidencoding the protein is a recombinant nucleic acid. In some embodiments,the protein is an antibody or a fragment thereof. Other exemplaryproteins can include, but are not limited to, enzymes, allergenicpeptides or proteins (for example, for use as a vaccine), recombinantprotein, cytokines, peptides, hormones, erythropoietin (EPO),interferons, granulocyte-colony stimulating factor (G-CSF),anticoagulants, and clotting factors. In some embodiments, theeukaryotic cell is a human embryonic kidney (HEK) cell or a Chinesehamster ovary (CHO) cell. In other embodiments, the eukaryotic cell is ayeast cell (such as Saccharomyces cerevisiae or Pichia pastoris), awheat germ cell, an insect cell, a rabbit reticulocyte, a cervicalcancer cell (such as a HeLa cell), a baby hamster kidney cell (such asBHK21 cells), a murine myeloma cell (such as NSO or Sp2/0 cells), anHT-1080 cell, a PER.C6 cell, a plant cell, a hybridoma cell, or a humanblood derived leukocyte.

In some embodiments, provided herein is a method of increasing proteintranslation in a cell or cell free expression system. In someembodiments, the cell was stressed prior to administration of thecompound, salt thereof, or composition. In some embodiments, proteintranslation is increased by at least about 10%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90%, 95%, 98%, 100%, 125%, 150%, 175%, 200%, 250%, or 300% ormore. In some embodiments, protein translation is increased by about 10%to about 300% (such as about 10% to about 20%, about 20% to about 30%,about 30% to about 40%, about 40% to about 50%, about 50% to about 60%,about 60% to about 70%, about 70% to about 80%, about 80% to about 90%,about 90% to about 100%, about 100% to about 125%, about 125% to about150%, about 150% to about 175%, about 175% to about 200%, about 200% toabout 250%, or about 250% to about 300%) In some embodiments, proteintranslation is increased as compared to prior to the administration ofthe compounds, salt thereof, or composition. In some embodiments,protein translation is increased as compared to an unstressed cell, abasal condition where cells are not subjected to a specific stress thatactivates the ISR. In some embodiments, protein translation is increasedas compared to a stressed cell where ISR is active.

Some of the compounds described herein increase protein synthesis in acell without full inhibition of ATF4 translation, under ISR-stressed ornon-ISR stressed conditions. Exemplary compounds include compound 150,compound 153, and compound 30, or a salt thereof. Despite ATF4participation in various pathologies, the ATF4 protein is an importantfactor for restoring cellular homeostasis in stressed cells, for exampleduring oxidative stress response, cholesterol metabolism, proteinfolding amino acid synthesis, and autophagy. Thus, for certaintreatments, it may be preferable to limit ATF4 inhibition. In someembodiments, the compound is used to increase protein synthesis by about10% or more, about 20% or more, about 30% or more, about 40% or more,about 50% or more, about 60% or more, about 70% or more, about 80% ormore, about 90% or more, about 100% or more, about 125% or more, about150% or more, about 175% or more, about 200% or more, about 250% ormore, or about 300% or more wherein ATF4 protein expression is inhibitedby about 75% or less, about 50% or less, about 40% or less, about 30% orless, about 20% or less, about 10% or less, or about 5% or less. In someembodiments the compound is used to increase protein synthesis by about10% to about 300% (such as about 10% to about 20%, about 20% to about30%, about 30% to about 40%, about 40% to about 50%, about 50% to about60%, about 60% to about 70%, about 70% to about 80%, about 80% to about90%, about 90% to about 100%, about 100% to about 125%, about 125% toabout 150%, about 150% to about 175%, about 175% to about 200%, about200% to about 250%, or about 250% to about 300%), wherein ATF4 proteinexpression is inhibited by about 75% or less (such as about 50% or less,about 40% or less, about 30% or less, about 20% or less, about 10% orless, or about 5% or less).

In some embodiments, provided herein is a method of increasing proteintranslation in a cell. In some embodiments, the cell was stressed priorto administration of the compound, salt thereof, or composition. In someembodiments, protein translation is increased by at least about 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 100%, 125%, 150%,175%, 200%, 250%, or 300% or more. In some embodiments, proteintranslation is increased as compared to prior to the administration ofthe compounds, salt thereof, or composition. In some embodiments,protein translation is increased as compared to an unstressed cell, abasal condition where cells are not subjected to a specific stress thatactivates the ISR. In some embodiments, protein translation is increasedas compared to a stressed cell where ISR is active.

In some embodiments, provided herein is a method of increasing guaninenucleotide exchange factor (GEF) activity of eIF2B in cells. In someembodiments, provided herein is a method of delaying or preventingapoptosis in a cell. In some embodiments, provided herein is a method ofinhibiting translation of one or more mRNAs comprising a 5′ untranslatedregion (5′UTR) that contains at least one upstream open reading frame(uORF), encoding proteins with translational preferences, including butnot limited to ATF4, ATF2, ATF5, CHOP, GADD34, BACE-1, C/EBPa, orMAP1LC3B. In some embodiments, the mRNA encodes ATF4, BACE-1, GADD34, orCHOP. In some embodiments, the mRNA encodes ATF4.

In some embodiments, expression of ATF4, BACE-1, GADD34 or CHOP isinhibited. In some embodiments, expression of ATF4 is inhibited. In someembodiments, expression of Aβ is inhibited. ATF4 increases expressionof, among others, GADD45A, CDKN1A, and EIF4EBP1, which encode DDIT-1,p21, and 4E-BP1, respectively. These proteins induce musculoskeletaldisease (such as skeletal muscle atrophy), and can be modulated byinhibiting expression of ATF4. Accordingly, in some embodiments,expression of one or more of CDKN1A, GADD45A, or EIF4EBP1 is inhibited.

In some embodiments, the compound, salt thereof, or composition inhibitstranslation of one or more mRNAs comprising a 5′ untranslated region(5′UTR) comprising at least one upstream open reading frame (uORF) withan IC₅₀ of less than about 1 μM, such as less than about 750 nM, 600 nM,500 nM, 300 nM, 200 nM, 100 nM, 80 nM, 60 nM, 40 nM, 25 nM, or less. Insome embodiments, the compound, salt thereof, or composition inhibitstranslation of one or more mRNAs comprising a 5′ untranslated region(5′UTR) comprising at least one upstream open reading frame (uORF) withan IC₅₀ between about 1 nM and 1 μM, such as between about 10 nM and 600nM, 15 nM and 200 nM, or 20 nM and 180 nM.

In some embodiments, the compound, salt thereof, or composition inhibitsexpression of ATF4 with an IC₅₀ of less than about 1 μM, such as lessthan about 750 nM, 600 nM, 500 nM, 300 nM, 200 nM, 100 nM, 80 nM, 60 nM,40 nM, 25 nM, or less. In some embodiments, the compound, salt thereof,or composition inhibits expression of ATF4 with an IC₅₀ between about 1nM and 1 μM, such as between about 2 nM and 800 nM, 10 nM and 600 nM, 15nM and 200 nM, or 20 nM and 180 nM.

In some aspects, the half maximal inhibitory concentration (IC₅₀) is ameasure of the effectiveness of a substance in inhibiting a specificbiological or biochemical function. In some aspects, the IC₅₀ is aquantitative measure that indicates how much of an inhibitor is neededto inhibit a given biological process or component of a process such asan enzyme, cell, cell receptor or microorganism by half. Methods ofdetermining IC₅₀ in vitro and in vivo are known in the art.

In some embodiments, the individual is a mammal. In some embodiments,the individual is a primate, bovine, ovine, porcine, equine, canine,feline, rabbit, or rodent. In some embodiments, the individual is ahuman. In some embodiments, the individual has any of the diseases ordisorders disclosed herein. In some embodiments, the individual is arisk for developing any of the diseases or disorders disclosed herein.

In some embodiments, the individual is human. In some embodiments, thehuman is at least about or is about any of 21, 25, 30, 35, 40, 45, 50,55, 60, 65, 70, 75, 80, or 85 years old. In some embodiments, the humanis a child. In some embodiments, the human is less than about or aboutany of 21, 18, 15, 12, 10, 8, 6, 5, 4, 3, 2, or 1 years old.

Also provided herein are uses of a compound described herein or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition described herein, in the manufacture of a medicament. Insome embodiments, the manufacture of a medicament is for the treatmentof a disorder or disease described herein. In some embodiments, themanufacture of a medicament is for the prevention and/or treatment of adisorder or disease mediated by an ISR pathway. In some embodiments, themanufacture of a medicament is for the prevention and/or treatment of adisorder or disease mediated by eIF2α or eIF2B. In some embodiments, themanufacture of a medicament is for the prevention and/or treatment of adisorder or disease mediated by phosphorylation of eIF2α and/or the GEFactivity of eIF2B.

Combinations

In certain aspects, a compound described herein is administered to anindividual for treatment of a disease in combination with one or moreadditional pharmaceutical agents that can treat the disease. Forexample, in some embodiments, an effective amount of the compound isadministered to an individual for the treatment of cancer in combinationwith one or more additional anticancer agents.

In some embodiments, activity of the additional pharmaceutical agent(such as additional anticancer agent) is inhibited by an activated ISRpathway. An ISR inhibitor, such as one of the compounds describedherein, can inhibit the ISR pathway to enhance functionality of theadditional pharmaceutical agent. By way of example, certain BRAFinhibitors (e.g., vemurafenib or dabrafenib) activate the ISR pathway inBRAF-mutated melanoma cells (e.g., BRAF with a V600F mutation) throughthe expression of ATF4. In some embodiments, there is a method oftreating cancer comprising administering to an individual with cancer aneffective amount of a compound described herein in combination with aneffective amount of a BRAF inhibitor. In some embodiments, there is amethod of treating a BRAF-mutated melanoma comprising administering toan individual with a BRAF-mutated melanoma an effective amount of acompound described herein in combination with an effective amount of aBRAF inhibitor. In some embodiments, there is a method of treating aBRAF-mutated melanoma comprising administering to an individual with aBRAF-mutated melanoma an effective amount of a compound described hereinin combination with an effective amount of vemurafenib or dabrafenib.

As another example, certain anticancer agents (such asubiquitin-proteasome pathway inhibitors (such as bortezomib), Cox-2inhibitors (e.g., celecoxib), platinum-based antineoplastic drugs (e.g.,cisplatin), anthracyclines (e.g. doxorubicin), or topoisomeraseinhibitors (e.g., etoposide)) are used to treat cancer, but may havelimited functionality against solid tumors. Resistance in certain solidtumors (e.g., breast cancers) has been associated with ATF4stabilization and induction of autophagy. In some embodiments, aneffective amount of an ISR inhibitor compound as described herein isadministered to an individual with cancer to increase sensitivity to oneor more anticancer agents.

In some embodiments, there is a method of treating a refractory cancer(such as a solid tumor) in an individual, comprising administering tothe individual an effective amount of a compound described herein incombination with an effective amount of an anticancer agent. In someembodiments, there is a method of treating a refractory cancer (such asa solid tumor) in an individual, comprising administering to theindividual an effective amount of a compound described herein incombination with an effective amount of an ubiquitin-proteasome pathwayinhibitor (e.g., bortezomib), a Cox-2 inhibitor (e.g., celecoxib), aplatinum-based antineoplastic drug (e.g., cisplatin), an anthracycline(e.g. doxorubicin), or a topoisomerase inhibitor (e.g., etoposide). Insome embodiments, the refractory cancer is breast cancer. In someembodiments, the refractory cancer is melanoma.

In some embodiments, a compound described herein is used to treat cancerin combination with one or more anti-cancer agents, such as ananti-neoplastic agent, an immune checkpoint inhibitor, or any othersuitable anti-cancer agent. Exemplary immune checkpoint inhibitorsinclude anti-PD-1, anti-PD-L1, anti GITR, anti-OX-40, anti-LAG3,anti-TIM-3, anti-41BB, anti-CTLA-4 antibodies. Exemplary anti-neoplasticagents can include, for example, anti-microtubule agents, platinumcoordination complexes, alkylating agents, topoisomerase II inhibitors,topoisomerase I inhibitors, antimetabolites, antibiotic agents, hormonesand hormonal analogs, signal transduction pathway inhibitors,non-receptor tyrosine kinase angiogenesis inhibitors, proteasomeinhibitors, and inhibitors of cancer metabolism. Other anti-canceragents can include one or more of an immuno-stimulant, an antibody orfragment thereof (e.g., an anti-CD20, anti-HER2, anti-CD52, or anti-VEGFantibody or fragment thereof), or an immunotoxin (e.g., an anti-CD33antibody or fragment thereof, an anti-CD22 antibody or fragment thereof,a calicheamicin conjugate, or a pseudomonas exotoxin conjugate).

ATF4-mediated expression of CHOP has also been shown to regulate thefunction and accumulation of myeloid-derived suppressor cells (MDSCs) intumors. MDSCs in tumors reduce the ability to prime T cell function andreduce antitumoral or anticancer responses. Certain immunotherapeuticagents (such as anti-PD-1, anti PD-L1, anti-GITR, anti-OX-40, anti-LAG3,anti-TIM-3, anti-41BB, or anti-CTLA-4 antibodies) have been used toboost the immune response against cancer. ATF4-mediated expression ofAXL has been associated with poor response to anti-PD1 therapy inmelanoma. In some embodiments, an effective amount of an ISR inhibitorcompound as described herein is administered to an individual withcancer to increase sensitivity to one or more immunotherapeutic agents.In some embodiments, there is a method of treating a refractory cancer(such as a melanoma) in an individual, comprising administering to theindividual an effective amount of a compound described herein incombination with an effective amount of an immunotherapeutic agent (e.g.anti-PD-1, anti PD-L1, anti-GITR, anti-OX-40, anti-LAG3, anti-TIM-3,anti-41BB, or anti-CTLA-4 antibodies). In some embodiments, therefractory cancer is melanoma.

Dosing and Method of Administration

The dose of a compound administered to an individual (such as a human)may vary with the particular compound or salt thereof, the method ofadministration, and the particular disease, such as type and stage ofcancer, being treated. In some embodiments, the amount of the compoundor salt thereof is a therapeutically effective amount.

The effective amount of the compound may in one aspect be a dose ofbetween about 0.01 and about 100 mg/kg. Effective amounts or doses ofthe compounds of the present disclosure may be ascertained by routinemethods, such as modeling, dose escalation, or clinical trials, takinginto account routine factors, e.g., the mode or route of administrationor drug delivery, the pharmacokinetics of the agent, the severity andcourse of the disease to be treated, the subject's health status,condition, and weight. An exemplary dose is in the range of about fromabout 0.7 mg to 7 g daily, or about 7 mg to 350 mg daily, or about 350mg to 1.75 g daily, or about 1.75 to 7 g daily.

Any of the methods provided herein may in one aspect compriseadministering to an individual a pharmaceutical composition thatcontains an effective amount of a compound provided herein or a saltthereof and a pharmaceutically acceptable excipient.

A compound or composition provided herein may be administered to anindividual in accordance with an effective dosing regimen for a desiredperiod of time or duration, such as at least about one month, at leastabout 2 months, at least about 3 months, at least about 6 months, or atleast about 12 months or longer, which in some variations may be for theduration of the individual's life. In one variation, the compound isadministered on a daily or intermittent schedule. The compound can beadministered to an individual continuously (for example, at least oncedaily) over a period of time. The dosing frequency can also be less thanonce daily, e.g., about a once weekly dosing. The dosing frequency canbe more than once daily, e.g., twice or three times daily. The dosingfrequency can also be intermittent, including a ‘drug holiday’ (e.g.,once daily dosing for 7 days followed by no doses for 7 days, repeatedfor any 14 day time period, such as about 2 months, about 4 months,about 6 months or more). Any of the dosing frequencies can employ any ofthe compounds described herein together with any of the dosagesdescribed herein.

Articles of Manufacture and Kits

The present disclosure further provides articles of manufacturecomprising a compound described herein or a salt thereof, a compositiondescribed herein, or one or more unit dosages described herein insuitable packaging. In certain embodiments, the article of manufactureis for use in any of the methods described herein. Suitable packaging isknown in the art and includes, for example, vials, vessels, ampules,bottles, jars, flexible packaging and the like. An article ofmanufacture may further be sterilized and/or sealed.

The present disclosure further provides kits for carrying out themethods of the present disclosure, which comprises one or more compoundsdescribed herein or a composition comprising a compound describedherein. The kits may employ any of the compounds disclosed herein. Inone variation, the kit employs a compound described herein or a saltthereof. The kits may be used for any one or more of the uses describedherein, and, accordingly, may contain instructions for the treatment ofany disease or described herein, for example for the treatment ofcancer.

Kits generally comprise suitable packaging. The kits may comprise one ormore containers comprising any compound described herein. Each component(if there is more than one component) can be packaged in separatecontainers or some components can be combined in one container wherecross-reactivity and shelf life permit.

The kits may be in unit dosage forms, bulk packages (e.g., multi-dosepackages) or sub-unit doses. For example, kits may be provided thatcontain sufficient dosages of a compound as disclosed herein and/or anadditional pharmaceutically active compound useful for a diseasedetailed herein to provide effective treatment of an individual for anextended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9months, or more. Kits may also include multiple unit doses of thecompounds and instructions for use and be packaged in quantitiessufficient for storage and use in pharmacies (e.g., hospital pharmaciesand compounding pharmacies).

The kits may optionally include a set of instructions, generally writteninstructions, although electronic storage media (e.g., magnetic disketteor optical disk) containing instructions are also acceptable, relatingto the use of component(s) of the methods of the present disclosure. Theinstructions included with the kit generally include information as tothe components and their administration to an individual.

General Synthetic Methods

The compounds of the present disclosure may be prepared by a number ofprocesses as generally described below and more specifically in theExamples hereinafter (such as the schemes provided in the Examplesbelow). In the following process descriptions, the symbols when used inthe formulae depicted are to be understood to represent those groupsdescribed above in relation to the formulae herein.

Where it is desired to obtain a particular enantiomer of a compound,this may be accomplished from a corresponding mixture of enantiomersusing any suitable conventional procedure for separating or resolvingenantiomers. Thus, for example, diastereomeric derivatives may beproduced by reaction of a mixture of enantiomers, e.g., a racemate, andan appropriate chiral compound. The diastereomers may then be separatedby any convenient means, for example by crystallization and the desiredenantiomer recovered. In another resolution process, a racemate may beseparated using chiral High-Performance Liquid Chromatography.Alternatively, if desired a particular enantiomer may be obtained byusing an appropriate chiral intermediate in one of the processesdescribed.

Chromatography, recrystallization and other conventional separationprocedures may also be used with intermediates or final products whereit is desired to obtain a particular isomer of a compound or tootherwise purify a product of a reaction.

Solvates and/or polymorphs of a compound provided herein or a saltthereof are also contemplated. Solvates contain either stoichiometric ornon-stoichiometric amounts of a solvent, and are often formed during theprocess of crystallization. Hydrates are formed when the solvent iswater, or alcoholates are formed when the solvent is alcohol. Polymorphsinclude the different crystal packing arrangements of the same elementalcomposition of a compound. Polymorphs usually have different X-raydiffraction patterns, infrared spectra, melting points, density,hardness, crystal shape, optical and electrical properties, stability,and/or solubility. Various factors such as the recrystallizationsolvent, rate of crystallization, and storage temperature may cause asingle crystal form to dominate.

Chromatography, recrystallization and other conventional separationprocedures may also be used with intermediates or final products whereit is desired to obtain a particular isomer of a compound or tootherwise purify a product of a reaction.

General methods of preparing compounds according to the presentdisclosure are depicted in the schemes below.

Compounds disclosed herein, such as compounds of formula (C-3), (C-4),(C-5), and (C-6), for example, can be synthesized according to thegeneral method described in the scheme above. A compound of formula(C-1) is reacted with a carboxylic acid (B-1a), or a carboxylic acidderivative (e.g. an acyl chloride of formula (B-1b), under suitableconditions to give a compound of formula (C-2). The compound of formula(C-2), which may first be optionally deprotected, is reacted with acarboxylic acid (B-2a), or a carboxylic acid derivative (e.g. an acylchloride of formula (B-2b), to give a compound of formula (C-3). Thecompound of formula (C-2), which may first be optionally deprotected, isreacted with an oxirane derivative of formula (B-3) to give a compoundof formula (C-4). The compound of formula (C-2), which may first beoptionally deprotected, is reacted with a haloalkyl derivative, such asa bromoalkyl compound of formula (B-4), to give a compound of formula(C-5). The compound of formula (C-2), which may first be optionallydeprotected, is reacted with a carboxylic acid (B-5a), or a carboxylicacid derivative (e.g. an acyl chloride of formula (B-5b), to give acompound of formula (C-6).

Compounds disclosed herein, such as compounds of formula (D-3), (D-4),(D-5), and (D-6), for example, can be synthesized according to thegeneral method described in the scheme above. A compound of formula(D-1) is reacted with a carboxylic acid (B-1a), or a carboxylic acidderivative (e.g. an acyl chloride of formula (B-1b), under suitableconditions to give a compound of formula (D-2). The compound of formula(D-2), which may first be optionally deprotected, is reacted with acarboxylic acid (B-2a), or a carboxylic acid derivative (e.g. an acylchloride of formula (B-2b), to give a compound of formula (D-3). Thecompound of formula (D-2), which may first be optionally deprotected, isreacted with an oxirane derivative of formula (B-3) to give a compoundof formula (D-4). The compound of formula (D-2), which may first beoptionally deprotected, is reacted with a haloalkyl derivative, such asa bromoalkyl compound of formula (B-4), to give a compound of formula(D-5). The compound of formula (D-2), which may first be optionallydeprotected, is reacted with a carboxylic acid (B-5a), or a carboxylicacid derivative (e.g. an acyl chloride of formula (B-5b), to give acompound of formula (D-6).

Compounds disclosed herein, such as compounds of formula (E-3), (E-4),(E-5), and (E-6), for example, can be synthesized according to thegeneral method described in the scheme above. A compound of formula(E-1) is reacted with a carboxylic acid (B-1a), or a carboxylic acidderivative (e.g. an acyl chloride of formula (B-1b), under suitableconditions to give a compound of formula (E-2). The compound of formula(E-2), which may first be optionally deprotected, is reacted with acarboxylic acid (B-2a), or a carboxylic acid derivative (e.g. an acylchloride of formula (B-2b), to give a compound of formula (E-3). Thecompound of formula (E-2), which may first be optionally deprotected, isreacted with an oxirane derivative of formula (B-3) to give a compoundof formula (E-4). The compound of formula (E-2), which may first beoptionally deprotected, is reacted with a haloalkyl derivative, such asa bromoalkyl compound of formula (B-4), to give a compound of formula(E-5). The compound of formula (E-2), which may first be optionallydeprotected, is reacted with a carboxylic acid (B-5a), or a carboxylicacid derivative (e.g. an acyl chloride of formula (B-5b), to give acompound of formula (E-6).

Compounds disclosed herein, such as compounds of formula (F-3), (F-4),(F-5), and (F-6), for example, can be synthesized according to thegeneral method described in the scheme above. A compound of formula(F-1) is reacted with a carboxylic acid (B-1a), or a carboxylic acidderivative (e.g. an acyl chloride of formula (B-1b), under suitableconditions to give a compound of formula (F-2). The compound of formula(F-2), which may first be optionally deprotected, is reacted with acarboxylic acid (B-2a), or a carboxylic acid derivative (e.g. an acylchloride of formula (B-2b), to give a compound of formula (F-3). Thecompound of formula (F-2), which may first be optionally deprotected, isreacted with an oxirane derivative of formula (B-3) to give a compoundof formula (F-4). The compound of formula (F-2), which may first beoptionally deprotected, is reacted with a haloalkyl derivative, such asa bromoalkyl compound of formula (B-4), to give a compound of formula(F-5). The compound of formula (F-2), which may first be optionallydeprotected, is reacted with a carboxylic acid (B-5a), or a carboxylicacid derivative (e.g. an acyl chloride of formula (B-5b), to give acompound of formula (F-6).

Compounds disclosed herein, such as compounds of formula (G-3), (G-4),(G-5), and (G-6), for example, can be synthesized according to thegeneral method described in the scheme above. A compound of formula(G-1) is reacted with a carboxylic acid (B-1a), or a carboxylic acidderivative (e.g. an acyl chloride of formula (B-1b), under suitableconditions to give a compound of formula (G-2). The compound of formula(G-2), which may first be optionally deprotected, is reacted with acarboxylic acid (B-2a), or a carboxylic acid derivative (e.g. an acylchloride of formula (B-2b), to give a compound of formula (G-3). Thecompound of formula (G-2), which may first be optionally deprotected, isreacted with an oxirane derivative of formula (B-3) to give a compoundof formula (G-4). The compound of formula (G-2), which may first beoptionally deprotected, is reacted with a haloalkyl derivative, such asa bromoalkyl compound of formula (B-4), to give a compound of formula(G-5). The compound of formula (G-2), which may first be optionallydeprotected, is reacted with a carboxylic acid (B-5a), or a carboxylicacid derivative (e.g. an acyl chloride of formula (B-5b), to give acompound of formula (G-6).

ENUMERATED EMBODIMENTS

The following enumerated embodiments are representative of some aspectsof the invention.

Embodiment 1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof;wherein:

-   -   X¹ and X², independently of each other, are CH or N;    -   Y¹ is selected from the group consisting of a bond, NR^(Y1), and        O; provided that when X¹ is N, then Y¹ is a bond;    -   R^(Y1) is hydrogen or C₁-C₆ alkyl;    -   Y² is selected from the group consisting of a bond, NR^(Y2), and        O; provided that when X² is N, then Y² is a bond;    -   R^(Y2) is hydrogen or C₁-C₆ alkyl;    -   m¹, m², n¹, n², p¹, p², q¹, and q², independently of each other,        are 0 or 1;    -   r and s, independently of each other, are 0, 1, or 2;    -   A¹ is selected from the group consisting of:        -   a substituent of formula (A¹-a)

-   -   -   -   wherein                -   * represents the attachment point to the remainder                    of the molecule;                -   Z¹ is selected from the group consisting of                    CR^(Z1-1)R^(Z1-2), NR^(Z1-2), O, S, and                    —CR^(Z1-1)═CR^(Z1-1)—;                -    wherein R^(Z1-1) is H or R¹⁴; and R^(Z1-2) is H or                    R¹⁴;                -   Z² is selected from the group consisting of                    CR^(Z2-1)R^(Z2-2), NR^(Z2-2); O S, and                    —CR^(Z2-1)═CR^(Z2-1)—;                -    wherein R^(Z2-1) is H or R¹⁴; and R^(Z2-2) is H or                    R¹⁴;                -   Z³, independently at each occurrence, is C or N,                    provided that at least one Z³ is C;                -   R¹³ is hydrogen or R¹⁴, or R¹³ and R^(Z1-2) are                    taken together to form a double bond between the                    carbon atom bearing R¹³ and Z¹, or R¹³ and R^(Z2-2)                    are taken together to form a double bond between the                    carbon atom bearing R¹³ and Z²; and                -   x1 is 0, 1, 2, 3, or 4, provided than when one Z³ is                    N, then x1 is not 4;

        -   C₆-C₁₀ aryl optionally substituted with one or more R¹⁴            substituents; and 5-10 membered heteroaryl optionally            substituted with one or more R¹⁴ substituents;

    -   R¹⁴ is selected, independently at each occurrence, from the        group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OH,        —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆ alkyl),        —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —NH(C₁-C₆        haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂,        —NR^(14-a)R^(14-b), —CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl),        —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),        —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆        haloalkyl)₂, —C(O)NR^(14-a)R^(14-b), —S(O)₂OH, —S(O)₂O(C₁-C₆        alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆        alkyl), —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,        —S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(14-a)R^(14-b), —OC(O)H,        —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H,        —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)C(O)H, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆        alkyl)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆        haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆        haloalkyl), —OS(O)₂(C₁-C₆ alkyl), —OS(O)₂(C₁-C₆ haloalkyl),        —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl),        —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆        haloalkyl)S(O)₂(C₁-C₆ haloalkyl);        -   wherein R^(14-a) and R^(14-b) are taken together with the            nitrogen atom which bears them to form a 3-10 membered            heterocycle;

    -   A² is selected from the group consisting of:        -   a substituent of formula (A²-a)

-   -   -   -   wherein                -   * represents the attachment point to the remainder                    of the molecule;                -   Z⁴ is selected from the group consisting of                    CR^(Z4-1)R^(Z4-2), NR^(Z4-2), O, S, and                    —CR^(Z4-1)═CR^(Z4-1)—,                -    wherein R^(Z4-1) is H or R¹⁶; and R^(Z4-2) is H or                    R¹⁶;                -   Z⁵ is selected from the group consisting of                    CR^(Z5-1)R^(Z5-2), NR^(Z5-2); O S, and                    —CR^(Z5-1)═CR^(Z5-1)—;                -    wherein R^(Z5-1) is H or R¹⁶; and R^(Z5-2) is H or                    R¹⁶;                -   Z⁶, independently at each occurrence, is C or N,                    provided that at least one Z⁶ is C;                -   R¹⁵ is hydrogen or R¹⁶, or R¹⁵ and R^(Z4-2) are                    taken together to form a double bond between the                    carbon atom bearing R¹⁵ and Z⁴, or R¹⁵ and R^(Z5-2)                    are taken together to form a double bond between the                    carbon atom bearing R¹⁵ and Z⁵; and                -   x2 is 0, 1, 2, 3, or 4, provided than when one Z⁶ is                    N, then x2 is not 4;

        -   C₆-C₁₀ aryl optionally substituted with one or more R¹⁶            substituents; and

        -   5-10 membered heteroaryl optionally substituted with one or            more R¹⁶ substituents;

    -   R¹⁶ is selected, independently at each occurrence, from the        group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OH,        —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆ alkyl),        —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —NH(C₁-C₆        haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂,        —NR^(16-a)R^(16-b); —CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl),        —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),        —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆        haloalkyl)₂, —C(O)NR^(16-a)R^(16-b); —S(O)₂OH, —S(O)₂O(C₁-C₆        alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆        alkyl), —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,        —S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(16-a)R^(16-b), —OC(O)H,        —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H,        —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)C(O)H, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆        alkyl)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆        haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆        haloalkyl), —OS(O)₂(C₁-C₆ alkyl), —OS(O)₂(C₁-C₆ haloalkyl),        —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl),        —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆        haloalkyl)S(O)₂(C₁-C₆ haloalkyl);        -   wherein R^(16-a) and R^(16-b) are taken together with the            nitrogen atom which bears them to form a 3-10 membered            heterocycle;

    -   R^(1a) and R^(1b) are independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, and halogen;

    -   R^(2a) and R^(2b) are independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, and halogen;

    -   when present, R^(3a) and R^(3b) are independently at each        occurrence selected from the group consisting of hydrogen, C₁-C₆        alkyl, and halogen;

    -   when present, R^(4a) and R^(4b) are independently at each        occurrence selected from the group consisting of hydrogen, C₁-C₆        alkyl, and halogen;

    -   or alternatively, R^(1a) and R^(2a) are taken together to form a        C₁-C₆ alkylene moiety;

    -   or alternatively, R^(1a) and an R^(3a) moiety, when present, are        taken together to form a C₁-C₆ alkylene moiety, and R^(1b) and        the R^(3b) in the geminal position to the R^(3a) taken together        with R^(1a), are both hydrogen;

    -   or alternatively, an R^(3a) moiety, when present, and an R^(4a)        moiety, when present, are taken together to form a C₁-C₆        alkylene moiety, and the R^(3b) in the geminal position to the        R^(3a) taken together with the R^(4a) moiety and the R^(4b) in        the geminal position to the R^(4a) taken together with the        R^(3a) moiety, are both hydrogen;

    -   when present, R^(5a) and R^(5b) are taken together to form an        oxo (═O) substituent or an imido (═NH) substituent, or        alternatively, R^(5a) and R^(5b) are both hydrogen;

    -   when present, R^(6a) is selected from the group consisting of        hydrogen, —OR^(6a-a), and —NR^(6a-b)R^(6a-c);

    -   when present, R^(6b) is hydrogen;

    -   or alternatively, R^(6a) and R^(6b) are taken together to form a        moiety selected from the group consisting of —O—CH₂—CH₂—,        —CH₂—O—CH₂—, —CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—, —CH₂—O—CH₂—CH₂—,        —CH₂—CH₂—O—CH₂—, —CH₂—CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—CH₂—,        —CH₂—O—CH₂—CH₂—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—CH₂—CH₂—O—CH₂—,        and —CH₂—CH₂—CH₂—CH₂—O—;

    -   when present, R^(7a) and R^(7b) are both hydrogen;

    -   when present, R^(8a) and R^(8b) are taken together to form an        oxo (═O) substituent, or alternatively, R^(8a) and R^(8b) are        both hydrogen;

    -   when present, R^(9a) and R^(9b) are taken together to form an        oxo (═O) substituent or an imido (═NH) substituent, or        alternatively, R^(9a) and R^(9b) are both hydrogen;

    -   when present, R^(10a) is selected from the group consisting of        hydrogen, —OR^(10a-a), and —NR^(10a-b)R^(10a-c);

    -   when present, R^(10b) is hydrogen;

    -   or alternatively, R^(10a) and R^(10b) are taken together to form        a moiety selected from the group consisting of —O—CH₂—CH₂—,        —CH₂—O—CH₂—, —CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—, —CH₂—O—CH₂—CH₂—,        —CH₂—CH₂—O—CH₂—, —CH₂—CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—CH₂—,        —CH₂—O—CH₂—CH₂—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—CH₂—CH₂—O—CH₂—,        and —CH₂—CH₂—CH₂—CH₂—O—;

    -   when present, R^(11a) and R^(11b) are both hydrogen;

    -   when present, R^(12a) and R^(12b) are taken together to form an        oxo (═O) substituent, or alternatively, R^(12a) and R^(12b) are        both hydrogen;

    -   R^(6a-a) is selected from the group consisting of hydrogen,        C₁-C₆ alkyl, and C₁-C₆ haloalkyl;

    -   R^(10a-a) is selected from the group consisting of hydrogen,        C₁-C₆ alkyl, and C₁-C₆ haloalkyl;

    -   or R^(6a-a) and R^(Y1) may be taken together to form a carbonyl        (C═O) moiety; or R^(10a-a) and R^(Y2) may be taken together to        form a carbonyl (C═O) moiety;

    -   R^(6-b) and R^(6a-c), independently of each other, are selected        from the group consisting of hydrogen, C₁-C₆ alkyl, and C₁-C₆        haloalkyl; and

    -   R^(10a-b) and R^(10a-c), independently of each other, are        selected from the group consisting of hydrogen, C₁-C₆ alkyl, and        C₁-C₆ haloalkyl.        Embodiment 2. The compound of embodiment 1, wherein the compound        of formula (I) is a compound of formula (1-1):

or a pharmaceutically acceptable salt thereof;wherein:

-   -   A¹ is a substituent of formula (A¹-a)

-   -   and    -   A² is a substituent of formula (A²-a)

Embodiment 3. The compound of embodiment 1, wherein the compound offormula (I) is a compound of formula (1-2):

or a pharmaceutically acceptable salt thereof;wherein:

-   -   A¹ is a substituent of formula (A¹-a)

-   -   and    -   A² is selected from the group consisting of:        -   a substituent of formula (A²-a)

-   -   -   C₆-C₁₀ aryl optionally substituted with one or more R¹⁶            substituents; and        -   5-10 membered heteroaryl optionally substituted with one or            more R¹⁶ substituents.            Embodiment 4. The compound of embodiment 1, wherein the            compound of formula (I) is a compound of formula (1-3):

or a pharmaceutically acceptable salt thereof;wherein:

-   -   A¹ is a substituent of formula (A¹-a)

and

A² is C₆-C₁₀ aryl optionally substituted with one or more R¹⁶substituents; or 5-10 membered heteroaryl optionally substituted withone or more R¹⁶ substituents.

Embodiment 5. The compound of embodiment 1, wherein the compound offormula (I) is a compound of formula (1-4):

or a pharmaceutically acceptable salt thereof;wherein:

-   -   A¹ is a substituent of formula (A¹-a)

-   -   A² is C₆-C₁₀ aryl optionally substituted with one or more R¹⁶        substituents; or 5-10 membered heteroaryl optionally substituted        with one or more R¹⁶ substituents;    -   R^(11a) and R^(11b) are both hydrogen; and    -   R^(12a) and R^(12b) are both hydrogen.        Embodiment 6. The compound of embodiment 1, wherein the compound        of formula (I) is a compound of formula (2-2):

or a pharmaceutically acceptable salt thereof;wherein:

-   -   A¹ is selected from the group consisting of:        -   a substituent of formula (A¹-a)

-   -   -   C₆-C₁₀ aryl optionally substituted with one or more R¹⁴            substituents; and        -   5-10 membered heteroaryl optionally substituted with one or            more R¹⁴ substituents;

    -   and

    -   A² is selected from the group consisting of:        -   a substituent of formula (A²-a)

-   -   -   C₆-C₁₀ aryl optionally substituted with one or more R¹⁶            substituents; and        -   5-10 membered heteroaryl optionally substituted with one or            more R¹⁶ substituents.            Embodiment 7. The compound of embodiment 1, wherein the            compound of formula (I) is a compound of formula (2-3):

or a pharmaceutically acceptable salt thereof;wherein:

-   -   A¹ is selected from the group consisting of:        -   a substituent of formula (A¹-a)

-   -   -   C₆-C₁₀ aryl optionally substituted with one or more R¹⁴            substituents; and        -   5-10 membered heteroaryl optionally substituted with one or            more R¹⁴ substituents;

    -   and

    -   A² is C₆-C₁₀ aryl optionally substituted with one or more R¹⁶        substituents; or 5-10 membered heteroaryl optionally substituted        with one or more R¹⁶ substituents.        Embodiment 8. The compound of embodiment 1, wherein the compound        of formula (I) is a compound of formula (2-4):

or a pharmaceutically acceptable salt thereof;wherein:

-   -   A¹ is selected from the group consisting of:        -   a substituent of formula (A¹-a)

-   -   -   C₆-C₁₀ aryl optionally substituted with one or more R¹⁴            substituents; and        -   5-10 membered heteroaryl optionally substituted with one or            more R¹⁴ substituents;

    -   A² is C₆-C₁₀ aryl optionally substituted with one or more R¹⁶        substituents; or 5-10 membered heteroaryl optionally substituted        with one or more R¹⁶ substituents;

    -   R^(11a) and R^(11b) are both hydrogen; and

    -   R^(12a) and R^(12b) are both hydrogen.        Embodiment 9. The compound of embodiment 1, wherein the compound        of formula (I) is a compound of formula (3-3):

or a pharmaceutically acceptable salt thereof;wherein:

-   -   A¹ is C₆-C₁₀ to aryl optionally substituted with one or more R¹⁴        substituents; or 5-10 membered heteroaryl optionally substituted        with one or more R¹⁴ substituents;    -   and    -   A² is C₆-C₁₀ aryl optionally substituted with one or more R¹⁶        substituents; or 5-10 membered heteroaryl optionally substituted        with one or more R¹⁶ substituents.        Embodiment 10. The compound of embodiment 1, wherein the        compound of formula (I) is a compound of formula (3-4):

or a pharmaceutically acceptable salt thereof;wherein:

-   -   A¹ is C₆-C₁₀ aryl optionally substituted with one or more R¹⁴        substituents; or 5-10 membered heteroaryl optionally substituted        with one or more R¹⁴ substituents;    -   A² is C₆-C₁₀ aryl optionally substituted with one or more R¹⁶        substituents; or 5-10 membered heteroaryl optionally substituted        with one or more R¹⁶ substituents;    -   R^(11a) and R^(11b) are both hydrogen; and    -   R^(12a) and R^(12b) are both hydrogen.        Embodiment 11. The compound of embodiment 1, wherein the        compound of formula (I) is a compound of formula (4-4):

or a pharmaceutically acceptable salt thereof;wherein:

-   -   A¹ is C₆-C₁₀ aryl optionally substituted with one or more R¹⁴        substituents; or 5-10 membered heteroaryl optionally substituted        with one or more R¹⁴ substituents;    -   A² is C₆-C₁₀ aryl optionally substituted with one or more R¹⁶        substituents; or 5-10 membered heteroaryl optionally substituted        with one or more R¹⁶ substituents;    -   R^(7a) and R^(7b) are both hydrogen;    -   R^(8a) and R^(8b) are both hydrogen;    -   R^(11a) and R^(11b) are both hydrogen; and    -   R^(12a) and R^(12b) are both hydrogen.        Embodiment 12. A compound of formula (II):

or a pharmaceutically acceptable salt thereof;wherein:

-   -   m3 is 0 or 1;    -   n3 is 0 or 1;    -   r2 is 0, 1, or 2;    -   s2 is 0, 1, or 2;    -   X³ is CH or N;    -   X⁴ is CH or N;    -   provided that at least one of X³ and X⁴ is CH;    -   Y³ is selected from the group consisting of a bond, NR^(Y3), and        O;        -   wherein R^(Y3) is hydrogen or C₁-C₆ alkyl;    -   Y⁴ is selected from the group consisting of a bond, NR^(Y4), and        O;        -   wherein R^(Y4) is hydrogen or C₁-C₆ alkyl;    -   provided that:        -   when X³ is N, then Y³ is a bond and m3 is 1;        -   when X⁴ is N, then Y⁴ is a bond and n3 is 1;    -   A³ is selected from the group consisting of:        -   a substituent of the formula (A³-a)

-   -   -   wherein            -   * represents the attachment point to the remainder of                the molecule;            -   Z⁷ is selected from the group consisting of                CR^(Z7-1)R^(Z7-2), NR^(Z7-2), O, S, and                —CR^(Z7-1)═CR^(Z7-1)—;                -   wherein                -   R^(Z7-1) is H or R²⁷; and                -   R^(Z7-2) is H or R²⁷;            -   Z⁸ is selected from the group consisting of                CR^(Z8-1)R^(Z8-2), NR^(Z8-2); O, S, and                —CR^(Z8-1)═CR^(Z8-1)—;                -   wherein                -   R^(Z8-1) is H or R²⁷; and                -   R^(Z8-2) is H or R²⁷;            -   Z⁹, independently at each occurrence, is C or N,                provided that at least one Z⁹ is C;            -   R²⁶ is hydrogen or R²⁷, or R²⁶ and R^(Z7-2) are taken                together to form a double bond between the carbon atom                bearing R²⁶ and Z⁷; and            -   x3 is 0, 1, 2, 3, or 4, provided than when one Z⁹ is N,                then x3 is not 4;        -   C₆-C₁₀ aryl optionally substituted with one or more R²⁷            substituent; and 5-10 membered heteroaryl optionally            substituted with one or more R²⁷ substituent;            -   R²⁷ is selected, independently at each occurrence, from                the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆                haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl),                —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,                —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆                alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(27-a)R^(27-b), —CN,                —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),                —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆                haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆                haloalkyl)₂, —C(O)NR^(27-a)R^(27-b), —S(O)₂OH,                —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),                —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆                haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆                haloalkyl)₂, —S(O)₂NR^(27-a)R^(27-b), —OC(O)H,                —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(27-a) and R^(27-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;

    -   A⁴ is selected from the group consisting of:        -   a substituent of the formula (A⁴-a)

-   -   -   wherein            -   * represents the attachment point to the remainder of                the molecule;            -   Z¹⁰ is selected from the group consisting of                CR^(Z10-1)R^(Z10-2), NR^(Z10-2), O, S, and                —CR^(Z10-1)═CR^(Z10-1)—;                -   wherein                -   R^(Z10-1) is H or R²⁹; and                -   R^(Z10-2) is H or R²⁹;            -   Z¹¹ is selected from the group consisting of                CR^(Z11-1)R^(Z11-2), NR^(Z11-2), O, S, and                —CR^(Z11-1)═CR^(Z11-1)—,                -   wherein                -   R^(Z11-1) is H or R²⁹; and                -   R^(Z11-2) is H or R²⁹;            -   Z¹², independently at each occurrence, is C or N,                provided that at least one Z¹² is C;            -   R²⁸ is hydrogen or R²⁹, or R²⁸ and R^(Z10-2) are taken                together to form a double bond between the carbon atom                bearing R²⁸ and Z¹⁰; and            -   x4 is 0, 1, 2, 3, or 4, provided than when one Z¹² is N,                then x4 is not 4;        -   C₆-C₁₀ aryl optionally substituted with one or more R²⁹            substituent; and        -   5-10 membered heteroaryl optionally substituted with one or            more R²⁹ substituent;            -   R²⁹ is selected, independently at each occurrence, from                the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆                haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl),                —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,                —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆                alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(29-a)R^(29-b), —CN,                —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),                —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆                haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆                haloalkyl)₂, —C(O)NR^(29-a)R^(29-b), —S(O)₂OH,                —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),                —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆                haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆                haloalkyl)₂, —S(O)₂NR^(29-a)R^(29-b), —OC(O)H,                —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(29-a) and R^(29-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;

    -   R^(17a) and R^(17b) are independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, and halogen;

    -   R^(18a) and R^(18b) are independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, and halogen;

    -   when present, R^(19a) and R^(19b) are independently at each        occurrence selected from the group consisting of hydrogen, C₁-C₆        alkyl, and halogen;

    -   when present, R^(20a) and R^(20b) are independently at each        occurrence selected from the group consisting of hydrogen, C₁-C₆        alkyl, and halogen;

    -   or alternatively, R^(17a) and R^(18a) are taken together to form        a C₁-C₆ alkylene moiety;

    -   or alternatively, R^(17a) and an R^(19a) moiety, when present,        are taken together to form a C₁-C₆ alkylene moiety, and R^(17b)        and the R^(19b) in the geminal position to the R^(19a) taken        together with R^(17a), are both hydrogen;

    -   or alternatively, an R^(19a) moiety, when present, and an        R^(20a) moiety, when present, are taken together to form a C₁-C₆        alkylene moiety, and the R^(19b) in the geminal position to the        R^(19a) taken together with the R^(20a) moiety and the R^(20b)        in the geminal position to the R^(20a) taken together with the        R^(19a) moiety, are both hydrogen;

    -   R^(21a) and R^(21b) are taken together to form an oxo (═O)        substituent or an imido (═NH) substituent, or alternatively,        R^(21a) and R^(21b) are both hydrogen;

    -   when present, R^(22a) and R^(22b) are both hydrogen;

    -   R^(23a) and R^(23b) are taken together to form an oxo (═O)        substituent or an imido (═NH) substituent, or alternatively,        R^(23a) and R^(23b) are both hydrogen;

    -   when present, R^(24a) is selected from the group consisting of        hydrogen, —OH, and —NH₂;

    -   or alternatively, R^(24a) and R^(Y4) are taken together to form        a #—C(═O)—O— group, wherein # represent the attachment point to        the nitrogen atom bearing R^(Y4);

    -   when present, R^(24b) is hydrogen; and

    -   when present, R^(25a) and R^(25b) are both hydrogen;

    -   or alternatively, R^(25a), when present, and one R²⁹ of A⁴ are        taken together with the atoms connecting them to form a 5-6        membered heterocycloalkenyl optionally substituted with one or        more R²⁹ substituent, and R^(25b) is H;

    -   or alternatively, R^(25a), when present, R^(25b), when present,        and one R²⁹ of A⁴ are taken together with the atoms connecting        them to form a 5-6 membered heteroaryl optionally substituted        with one or more R²⁹ substituent;

    -   and further provided that one of (i), (ii), (iii) and (iv)        applies:

    -   (i) when m3 is 0 and n3 is 0, then:        -   X³ is CH and Y³ is NR^(Y3);        -   X⁴ is CH and Y⁴ is NR^(Y4);        -   R^(21a) and R^(21b) are taken together to form an oxo (═O)            substituent;        -   R^(23a) and R^(23b) are taken together to form an oxo (═O)            substituent;        -   A³ is a substituent of the formula (A³-a)

-   -   -   wherein            -   * represents the attachment point to the remainder of                the molecule;            -   Z⁷ is selected from the group consisting of                CR^(Z7-1)R^(Z7-2), NR^(Z7-2), O, S, and                —CR^(Z7-1)═CR^(Z7-1)—,                -   wherein                -   R^(Z7-1) is H or R²⁷; and                -   R^(Z7-2) is H or R²⁷;            -   Z⁸ is selected from the group consisting of                CR^(Z8-1)R^(Z8-2), NR^(Z8-2); O, S, and                CR^(Z8-1)═CR^(Z8-1)—;                -   wherein                -   R^(Z8-1) is H or R²⁷; and                -   R^(Z8-2) is H or R²⁷;            -   Z⁹, independently at each occurrence, is C or N,                provided that at least one Z⁹ is C;            -   R²⁶ is hydrogen or R²⁷, or R²⁶ and R^(Z7-2) are taken                together to form a double bond between the carbon atom                bearing R²⁶ and Z⁷;            -   R²⁷ is selected, independently at each occurrence, from                the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆                haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl),                —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,                —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆                alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(27-a)R^(27-b), —CN,                —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),                —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆                haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆                haloalkyl)₂, —C(O)NR^(27-a)R^(27-b), —S(O)₂OH,                —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),                —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆                haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆                haloalkyl)₂, —S(O)₂NR^(27-a)R^(27-b), —OC(O)H,                —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(27-a) and R^(27-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;            -   x3 is 0, 1, 2, 3, or 4, provided than when one Z⁹ is N,                then x3 is not 4;        -   A⁴ is a substituent of the formula (A⁴-a)

-   -   -   wherein            -   * represents the attachment point to the remainder of                the molecule;            -   Z¹⁰ is selected from the group consisting of                CR^(Z19-1)R^(Z10-2), NR^(Z10-2), O, S, and                —CR^(Z10-1)═CR^(Z10-1)—;                -   wherein                -   R^(Z19-1) is H or R²⁹; and                -   R^(Z19-2) is H or R²⁹;            -   Z¹¹ is selected from the group consisting of                CR^(Z11-1)R^(Z11-2), NR^(Z11-2); O, S, and                —CR^(Z11-1)═CR^(Z11-1)—;                -   wherein                -   R^(Z11-1) is H or R²⁹; and                -   R^(Z11-2) is H or R²⁹;            -   Z¹², independently at each occurrence, is C or N,                provided that at least one Z¹² is C;            -   R²⁸ is hydrogen or R²⁹, or R²⁸ and R^(Z10-2) are taken                together to form a double bond between the carbon atom                bearing R²⁸ and Z¹⁰;            -   R²⁹ is selected, independently at each occurrence, from                the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆                haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl),                —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,                —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆                alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(29-a)R^(29-b), —CN,                —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),                —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆                haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆                haloalkyl)₂, —C(O)NR^(29-a)R^(29-b), —S(O)₂OH,                —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),                —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆                haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆                haloalkyl)₂, —S(O)₂NR^(29-a)R^(29-b), —OC(O)H,                —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(29-a) and R^(29-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;            -   x4 is 0, 1, 2, 3, or 4, provided than when one Z¹² is N,                then x4 is not 4; and        -   provided that A³ and A⁴ are not both simultaneously a moiety            selected from group consisting of:

wherein the * represents the attachment point to the remainder of themolecule;

-   -   (ii) when m3 is 0 and n3 is 1, then:        -   r2 is 1 or 2;        -   s2 is 1 or 2;        -   X³ is CH and Y³ is NR^(Y3);        -   R^(21a) and R^(21b) are taken together to form an oxo (═O)            substituent;        -   R^(24a) is selected from the group consisting of hydrogen,            —OH, and —NH₂;        -   A³ is a substituent of the formula (A³-a)

-   -   -   wherein            -   * represents the attachment point to the remainder of                the molecule;            -   Z⁷ is selected from the group consisting of                CR^(Z7-1)R^(Z7-2), NR^(Z7-2), O, S, and                —CR^(Z7-1)═CR^(Z7-1)—;                -   wherein                -   R^(Z7-1) is H or R²⁷; and                -   R^(Z7-2) is H or R²⁷;            -   Z⁸ is selected from the group consisting of                CR^(Z8-1)R^(Z8-2), NR^(Z8-2), O, S, and                —CR^(Z8-1)═CR^(Z8-1)—;                -   wherein                -   R^(Z8-1) is H or R²⁷; and                -   R^(Z8-2) is H or R²⁷;            -   Z⁹, independently at each occurrence, is C or N,                provided that at least one Z⁹ is C;            -   R²⁶ is hydrogen or R²⁷, or R²⁶ and R^(Z7-2) are taken                together to form a double bond between the carbon atom                bearing R²⁶ and Z⁷;            -   R²⁷ is selected, independently at each occurrence, from                the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆                haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl),                —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,                —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆                alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(27-a)R^(27-b), —CN,                —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),                —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆                haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆                haloalkyl)₂, —C(O)NR^(27-a)R^(27-b), —S(O)₂OH,                —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),                —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆                haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆                haloalkyl)₂, —S(O)₂NR^(27-a)R^(27-b), —OC(O)H,                —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(27-a) and R^(27-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;            -   x3 is 0, 1, 2, 3, or 4, provided than when one Z⁹ is N,                then x3 is not 4;        -   A⁴ is C₆-C₁₀ aryl optionally substituted with one or more            R²⁹ substituent, or 5-10 membered heteroaryl optionally            substituted with one or more R²⁹ substituent;            -   R²⁹ is selected, independently at each occurrence, from                the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆                haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl),                —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,                —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆                alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(29-a)R^(29-b), —CN,                —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),                —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆                haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆                haloalkyl)₂, —C(O)NR^(29-a)R^(29-b), —S(O)₂OH,                —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),                —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆                haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆                haloalkyl)₂, —S(O)₂NR^(29-a)R^(29-b), —OC(O)H,                —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(29-a) and R^(29-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;        -   provided that when R^(23a) and R^(23b) are taken together to            form an oxo (═O) substituent, then R^(24a) is —OH or —NH₂;

    -   (iii) when m3 is 1 and n3 is 0, then:        -   X⁴ is CH and Y⁴ is NR^(Y4);        -   R^(21a) and R^(21b) are taken together to form an oxo (═O)            substituent or an imido (═NH) substituent;        -   R^(23a) and R^(23b) are taken together to form an oxo (═O)            substituent;        -   A³ is C₆-C₁₀ aryl optionally substituted with one or more            R²⁷ substituent, or 5-10 membered heteroaryl optionally            substituted with one or more R²⁷ substituent;            -   R²⁷ is selected, independently at each occurrence, from                the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆                haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl),                —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,                —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆                alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(27-a)R^(27-b), —CN,                —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),                —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆                haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆                haloalkyl)₂, —C(O)NR^(27-a)R^(27-b), —S(O)₂OH,                —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),                —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆                haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆                haloalkyl)₂, —S(O)₂NR^(27-a)R^(27-b), —OC(O)H,                —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(27-a) and R^(27-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;        -   A⁴ is a substituent of the formula (A⁴-a)

-   -   -   wherein            -   * represents the attachment point to the remainder of                the molecule;            -   Z¹⁰ is selected from the group consisting of                CR^(Z10-1)R^(Z10-2), NR^(Z10-2), O, S, and                —CR^(Z10-1)═CR^(Z10-1)—;                -   wherein                -   R^(Z10-1) is H or R²⁹; and                -   R^(Z10-2) is H or R²⁹;            -   Z¹¹ is selected from the group consisting of                CR^(Z11-1)R^(Z11-2), NR^(Z11-2), O, S, and                —CR^(Z11-1)═CR^(Z11-1)—;                -   wherein                -   R^(Z11-1) is H or R²⁹; and                -   R^(Z11-2) is H or R²⁹;            -   Z¹², independently at each occurrence, is C or N,                provided that at least one Z¹² is C;            -   R²⁸ is hydrogen or R²⁹, or R²⁸ and R^(Z10-2) are taken                together to form a double bond between the carbon atom                bearing R²⁸ and Z¹⁰;            -   R²⁹ is selected, independently at each occurrence, from                the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆                haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl),                —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,                —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆                alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(29-a)R^(29-b), —CN,                —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),                —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆                haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆                haloalkyl)₂, —C(O)NR^(29-a)R^(29-b), —S(O)₂OH,                —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),                —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆                haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆                haloalkyl)₂, —S(O)₂NR^(29-a)R^(29-b), —OC(O)H,                —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(29-a) and R^(29-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;            -   x4 is 0, 1, 2, 3, or 4, provided than when one Z¹² is N,                then x4 is not 4;

    -   (iv) when m3 is 1 and n3 is 1, then:        -   R^(21a) and R^(21b) are taken together to form an oxo (═O)            substituent or an imido (═NH) substituent;        -   A³ is C₆-C₁₀ aryl optionally substituted with one or more            R²⁷ substituent, or 5-10 membered heteroaryl optionally            substituted with one or more R²⁷ substituent;            -   R²⁷ is selected, independently at each occurrence, from                the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆                haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl),                —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,                —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆                alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(27-a)R^(27-b), —CN,                —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),                —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆                haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆                haloalkyl)₂, —C(O)NR^(27-a)R^(27-b), —S(O)₂OH,                —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),                —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆                haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆                haloalkyl)₂, —S(O)₂NR^(27-a)R^(27-b), —OC(O)H,                —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(27-a) and R^(27-b) are taken together                    with the nitrogen atom which bears them to form a                    3-10 membered heterocycle;        -   A⁴ is C₆-C₁₀ aryl optionally substituted with one or more            R²⁹ substituent, or 5-10 membered heteroaryl optionally            substituted with one or more R²⁹ substituent;            -   R²⁹ is selected, independently at each occurrence, from                the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆                haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl),                —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,                —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆                alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(29-a)R^(29-b), —CN,                —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),                —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆                haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆                haloalkyl)₂, —C(O)NR^(29-a)R^(29-b), —S(O)₂OH,                —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),                —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆                haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆                haloalkyl)₂, —S(O)₂NR^(29-a)R^(29-b), —OC(O)H,                —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl);                -   wherein R^(29-a) and R^(29-b) are taken together                    with the nitrogen atom            -   which bears them to form a 3-10 membered heterocycle;                provided that:            -   when one of X³ or X⁴ is N, then r2 is 1 or 2 and s2 is 1                or 2; and            -   when R^(23a) and R^(23b) are taken together to form an                oxo (═O) substituent, then R^(24a) is —OH or —NH₂.                Embodiment 12. A compound of formula (XX):

or a pharmaceutically acceptable salt thereof;wherein:

-   -   X⁵ is CH or N;    -   Y⁵ is selected from the group consisting of a bond, NR^(Y5), and        O; provided that when X⁵ is N, then Y⁵ is a bond;    -   R^(Y5) is hydrogen or C₁-C₆ alkyl;    -   R^(N) is hydrogen or C₁-C₆ alkyl;    -   m⁴, n⁵, p³, and q⁴, independently of each other, are 0 or 1;    -   r3 and s3, independently of each other, are 0, 1, or 2;    -   A¹³ is selected from the group consisting of:        -   C₆-C₁₀ aryl optionally substituted with one or more R⁹⁵            substituents; and        -   5-10 membered heteroaryl optionally substituted with one or            more R⁹⁵ substituents;    -   R⁹⁵ is selected, independently at each occurrence, from the        group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OH,        —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆ alkyl),        —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —NH(C₁-C₆        haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂,        —NR^(95-a)R^(95-b), —CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl),        —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),        —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆        haloalkyl)₂, —C(O)NR^(95-a)R^(95-b), —S(O)₂OH, —S(O)₂O(C₁-C₆        alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆        alkyl), —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,        —S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(95-a)R^(95-b), —OC(O)H,        —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H,        —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)C(O)H, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆        alkyl)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆        haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆        haloalkyl), —OS(O)₂(C₁-C₆ alkyl), —OS(O)₂(C₁-C₆ haloalkyl),        —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl),        —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆        haloalkyl)S(O)₂(C₁-C₆ haloalkyl);        -   wherein R^(95-a) and R^(95-b) are taken together with the            nitrogen atom which bears them to form a 3-10 membered            heterocycle;    -   R^(84a) and R^(84b) are independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, and halogen;    -   R^(85a) and R^(85b) are independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, and halogen;    -   when present, R^(86a) and R^(86b) are independently at each        occurrence selected from the group consisting of hydrogen, C₁-C₆        alkyl, and halogen;    -   when present, R^(87a) and R^(87b) are independently at each        occurrence selected from the group consisting of hydrogen, C₁-C₆        alkyl, and halogen;    -   or, R^(84a) and R^(85a) are taken together to form a C₁-C₆        alkylene moiety;    -   or, R^(84a) and an R^(86a) moiety, when present, are taken        together to form a C₁-C₆ alkylene moiety;    -   or, an R^(86a) moiety, when present, and an R^(87a) moiety, when        present, are taken together to form a C₁-C₆ alkylene moiety;    -   R⁸⁸ is selected from the group consisting of hydrogen, C₁-C₆        alkyl, C₁-C₆ haloalkyl, —C(O)(C₁-C₆ alkyl), —C(O)(C₁-C₆        haloalkyl), —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆        haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆        haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆ haloalkyl)₂,        —C(O)NR^(88-a)R^(88-b), —S(O)₂OH, —S(O)₂O(C₁-C₆ alkyl),        —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl),        —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆        haloalkyl)₂, and —S(O)₂NR^(88-a)R^(88-b);        -   wherein R^(88-a) and R^(88-b) are taken together with the            nitrogen atom which bears them to form a 3-10 membered            heterocycle;    -   R⁸⁹ is selected, independently at each occurrence, from the        group consisting of hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆        haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH,        —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl),        —NH(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂,        —NR^(89-a)R^(89-b), —CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl),        —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),        —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆        haloalkyl)₂, —C(O)NR^(89-a)R^(89-b), —S(O)₂OH, —S(O)₂O(C₁-C₆        alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆        alkyl), —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,        —S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR⁸⁹ aR^(89-b), —OC(O)H,        —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H,        —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)C(O)H, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆        alkyl)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆        haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆        haloalkyl), —OS(O)₂(C₁-C₆ alkyl), —OS(O)₂(C₁-C₆ haloalkyl),        —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl),        —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆        haloalkyl)S(O)₂(C₁-C₆ haloalkyl);    -   wherein R^(89-a) and R^(89-b) are taken together with the        nitrogen atom which bears them to form a 3-10 membered        heterocycle;    -   when present, R^(90a) and R^(90b) are taken together to form an        oxo (═O) substituent or an imido (═NH) substituent, or        alternatively, R^(90a) and R^(90b) are both hydrogen;    -   when present, R^(91a) is selected from the group consisting of        hydrogen, —OR^(91a-a), and NR^(91a-b)R^(91a-c);    -   when present, R^(91b) is hydrogen;    -   or alternatively, R^(91a) and R^(91b) are taken together to form        a moiety selected from the group consisting of —O—CH₂—CH₂—,        —CH₂—O—CH₂—, —CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—, —CH₂—O—CH₂—CH₂—,        —CH₂—CH₂—O—CH₂—, —CH₂—CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—CH₂—,        —CH₂—O—CH₂—CH₂—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—CH₂—CH₂—O—CH₂—,        and —CH₂—CH₂—CH₂—CH₂—O—;    -   when present, R^(92a) and R^(92b) are both hydrogen;    -   when present, R^(93a) and R^(93b) are taken together to form an        oxo (═O) substituent, or alternatively, R^(93a) and R^(93b) are        both hydrogen;    -   R^(91a-a) is selected from the group consisting of hydrogen,        C₁-C₆ alkyl, and C₁-C₆ haloalkyl;    -   or R^(91a-a) and R^(Y5) may be taken together to form a carbonyl        (C═O) moiety; and    -   R^(91a-b) and R^(91a-c), independently of each other, are        selected from the group consisting of hydrogen, C₁-C₆ alkyl, and        C₁-C₆ haloalkyl;    -   provided that when m⁴ is 0, n⁵ is 0, and q⁴ is 0, then p³ is 1        and A¹³ is a substituent of formula (A¹³-a)

-   -   -   wherein            -   * represents the attachment point to the remainder of                the molecule;            -   Z¹⁴ is selected from the group consisting of                CR^(Z14-1)R^(Z14-2), NR^(Z14-2),                C(R^(Z14-1)R^(Z14-2))N(R^(Z14-2)), O,                C(R^(Z14-1)R^(Z14-2))O, s, C(R^(Z14-1)R^(Z14-2))S, and                —CR^(Z14-1)═CR^(Z14-1)—;                -   wherein R^(Z14-1) is hydrogen or R¹⁶; and R^(Z14-2)                    is hydrogen or R⁹⁵;            -   Z¹⁵ is selected from the group consisting of                CR^(Z15-1)R^(Z15-2), NR^(Z15-2),                C(R^(Z15-1)R^(Z15-2))N(R^(Z15-2)), O,                C(R^(Z15-1)R^(Z15-2))O, S, C(R^(Z15-1)R^(Z15-2))S, and                —CR^(Z15-1)═CR^(Z15-1)—;                -   wherein R^(Z15-1) is hydrogen or R⁹⁵; and R^(Z15-2)                    is hydrogen or R⁹⁵;            -   Z¹⁶, independently at each occurrence, is CH, CR⁹⁵, or                N;            -   R⁹⁴ is hydrogen or R⁹⁵, or R⁹⁴ and R^(Z14-2) are taken                together to form a double bond between the carbon atom                bearing R⁹⁴ and Z¹⁴, or R⁹⁴ and R^(Z15-2) are taken                together to form a double bond between the carbon atom                bearing R⁹⁴ and Z¹⁵; and            -   x23 is 0, 1, 2, 3, or 4.                Embodiment 13. A compound selected from the group                consisting of a compound of Table 1, or a                pharmaceutically acceptable salt thereof.                Embodiment 14. A pharmaceutical composition comprising a                compound of any of the preceding embodiments, or a                pharmaceutically acceptable salt thereof, and a                pharmaceutically acceptable carrier.                Embodiment 15. A method of treating a disease or                disorder mediated by an integrated stress response (ISR)                pathway in an individual in need thereof comprising                administering to the individual a therapeutically                effective amount of a compound of any one of embodiments                1 to 13, or a pharmaceutically acceptable salt thereof,                or a therapeutically effective amount of a                pharmaceutical composition of embodiment 14.                Embodiment 16. The method of embodiment 14, wherein the                compound, the pharmaceutically acceptable salt, or the                pharmaceutical composition is administered in                combination with a therapeutically effective amount of                one or more additional anti-cancer agents.                Embodiment 17. The method of embodiment 15, wherein the                disease or disorder is mediated by phosphorylation of                eIF2α and/or the guanine nucleotide exchange factor                (GEF) activity of eIF2B.                Embodiment 18. The method of any one of embodiments                15-17, wherein the disease or disorder is mediated by a                decrease in protein synthesis.                Embodiment 19. The method of any one of embodiments                15-18, wherein the disease or disorder is mediated by                the expression of ATF4, CHOP or BACE-1.                Embodiment 20. The method of any of embodiments 15-19,                wherein the disease or disorder is a neurodegenerative                disease, an inflammatory disease, an autoimmune disease,                a metabolic syndrome, a cancer, a vascular disease, an                ocular disease, a musculoskeletal disease, or a genetic                disorder.                Embodiment 21. The method of embodiment 20, wherein the                disease is vanishing white matter disease, childhood                ataxia with CNS hypomyelination, intellectual disability                syndrome, Alzheimer's disease, prion disease,                Creutzfeldt-Jakob disease, Parkinson's disease,                amyotrophic lateral sclerosis (ALS) disease, cognitive                impairment, frontotemporal dementia (FTD), traumatic                brain injury, postoperative cognitive dysfunction (PCD),                neuro-otological syndromes, hearing loss, Huntington's                disease, stroke, chronic traumatic encephalopathy,                spinal cord injury, dementias or cognitive impairment,                arthritis, psoriatic arthritis, psoriasis, juvenile                idiopathic arthritis, asthma, allergic asthma, bronchial                asthma, tuberculosis, chronic airway disorder, cystic                fibrosis, glomerulonephritis, membranous nephropathy,                sarcoidosis, vasculitis, ichthyosis, transplant                rejection, interstitial cystitis, atopic dermatitis or                inflammatory bowel disease, Crohn's disease, ulcerative                colitis, celiac disease, systemic lupus erythematosus,                type 1 diabetes, multiple sclerosis, rheumatoid                arthritis, alcoholic liver steatosis, obesity, glucose                intolerance, insulin resistance, hyperglycemia, fatty                liver, dyslipidemia, hyperlipidemia, type 2 diabetes,                pancreatic cancer, breast cancer, kidney cancer, bladder                cancer, prostate cancer, testicular cancer, urothelial                cancer, endometrial cancer, ovarian cancer, cervical                cancer, renal cancer, esophageal cancer,                gastrointestinal stromal tumor (GIST), multiple myeloma,                cancer of secretory cells, thyroid cancer,                gastrointestinal carcinoma, chronic myeloid leukemia,                hepatocellular carcinoma, colon cancer, melanoma,                malignant glioma, glioblastoma, glioblastoma multiforme,                astrocytoma, dysplastic gangliocytoma of the cerebellum,                Ewing's sarcoma, rhabdomyosarcoma, ependymoma,                medulloblastoma, ductal adenocarcinoma, adenosquamous                carcinoma, nephroblastoma, acinar cell carcinoma, lung                cancer, non-Hodgkin's lymphoma, Burkitt's lymphoma,                chronic lymphocytic leukemia, monoclonal gammopathy of                undetermined significance (MGUS), plasmocytoma,                lymphoplasmacytic lymphoma, acute lymphoblastic                leukemia, Pelizaeus-Merzbacher disease, atherosclerosis,                abdominal aortic aneurism, carotid artery disease, deep                vein thrombosis, Buerger's disease, chronic venous                hypertension, vascular calcification, telangiectasia or                lymphoedema, glaucoma, age-related macular degeneration,                inflammatory retinal disease, retinal vascular disease,                diabetic retinopathy, uveitis, rosacea, Sjogren's                syndrome or neovascularization in proliferative                retinopathy, hyperhomocysteinemia, skeletal muscle                atrophy, myopathy, muscular dystrophy, muscular wasting,                sarcopenia, Duchenne muscular dystrophy (DMD), Becker's                disease, myotonic dystrophy, X-linked dilated                cardiomyopathy, spinal muscular atrophy (SMA), Down                syndrome, MEHMO syndrome, metaphyseal chondrodysplasia,                Schmid type (MCDS), depression, or social behavior                impairment.                Embodiment 22. A method of producing a protein,                comprising contacting a eukaryotic cell comprising a                nucleic acid encoding the protein with the compound or                salt of any one of embodiments 1-13.                Embodiment 23. The method of embodiment 22, comprising                culturing the cell in an in vitro culture medium                comprising the compound or salt.                Embodiment 24. A method of culturing a eukaryotic cell                comprising a nucleic acid encoding a protein, comprising                contacting the eukaryotic cell with an in vitro culture                medium comprising a compound or salt of any one of                embodiments 1-13.                Embodiment 25. The method of any one of embodiments                22-24, wherein the nucleic acid encoding the protein is                a recombinant nucleic acid.                Embodiment 26. The method of any one of embodiments                22-25, wherein the cell is a human embryonic kidney                (HEK) cell or a Chinese hamster ovary (CHO) cell.                Embodiment 27. The method of any one of embodiments                22-25, wherein the cell is a yeast cell, a wheat germ                cell, an insect cell, a rabbit reticulocyte, a cervical                cancer cell, a baby hamster kidney cell, a murine                myeloma cell, an HT-1080 cell, a PER.C6 cell, a plant                cell, a hybridoma cell, or a human blood derived                leukocyte                Embodiment 28. A method of producing a protein,                comprising contacting a cell-free protein synthesis                (CFPS) system comprising eukaryotic initiation factor 2                (eIF2) and a nucleic acid encoding a protein with the                compound or salt of any one of embodiments 1-13.                Embodiment 29. The method of any one of embodiments                22-28, wherein the protein is an antibody or a fragment                thereof.                Embodiment 30. The method of any one of embodiments                22-28, wherein the protein is a recombinant protein, an                enzyme, an allergenic peptide, a cytokine, a peptide, a                hormone, erythropoietin (EPO), an interferon, a                granulocyte-colony stimulating factor (G-CSF), an                anticoagulant, or a clotting factor.                Embodiment 31. The method of any one of embodiments                22-30, comprising purifying the protein.                Embodiment 32. An in vitro cell culture medium,                comprising the compound or salt of any one of                embodiments 1-13 and nutrients for cellular growth.                Embodiment 33. The cell culture medium of embodiment 32,                comprising a eukaryotic cell comprising a nucleic acid                encoding a protein.                Embodiment 34. The cell culture medium of embodiment 32                or 33, further comprising a compound for inducing                protein expression.                Embodiment 35. The cell culture medium of any one of                embodiments 32-34, wherein the nucleic acid encoding the                protein is a recombinant nucleic acid.                Embodiment 36. The cell culture medium of any one of                embodiments 32-35, wherein the protein is an antibody or                a fragment thereof.                Embodiment 37. The cell culture medium of any one of                embodiments 32-35, wherein the protein is a recombinant                protein, an enzyme, an allergenic peptide, a cytokine, a                peptide, a hormone, erythropoietin (EPO), an interferon,                a granulocyte-colony stimulating factor (G-CSF), an                anticoagulant, or a clotting factor.                Embodiment 38. The cell culture medium of any one of                embodiments 32-37, wherein the eukaryotic cell is a                human embryonic kidney (HEK) cell or a Chinese hamster                ovary (CHO) cell.                Embodiment 39. The cell culture medium of any one of                embodiments 32-37, wherein the cell is a yeast cell, a                wheat germ cell, an insect cell, a rabbit reticulocyte,                a cervical cancer cell, a baby hamster kidney cell, a                murine myeloma cell, an HT-1080 cell, a PER.C6 cell, a                plant cell, a hybridoma cell, or a human blood derived                leukocyte                Embodiment 40. A cell-free protein synthesis (CFPS)                system comprising eukaryotic initiation factor 2 (eIF2)                and a nucleic acid encoding a protein with the compound                or salt of any one of embodiments 1-13.                Embodiment 41. The CFPS system of embodiment 40,                comprising a eukaryotic cell extract comprising eIF2.                Embodiment 42. The CFPS system of embodiment 40 or 41,                further comprising eIF2B.                Embodiment 43. The CFPS system of any one of embodiments                40-42, wherein the protein is an antibody or a fragment                thereof.                Embodiment 44. The CFPS system of any one of embodiments                40-43, wherein the protein is a recombinant protein, an                enzyme, an allergenic peptide, a cytokine, a peptide, a                hormone, erythropoietin (EPO), an interferon, a                granulocyte-colony stimulating factor (G-CSF), an                anticoagulant, or a clotting factor.                Embodiment 1A. A compound of formula (1-2):

or a pharmaceutically acceptable salt thereof;wherein:

-   -   X² is CH;    -   R^(Y1) is hydrogen or C₁-C₆ alkyl;    -   Y² is selected from the group consisting of NR^(Y2) and O;    -   R^(Y2) is hydrogen or C₁-C₆ alkyl;    -   q² is 1;    -   r and s, independently of each other, are 0, 1, or 2;    -   A¹ is a substituent of formula (A¹-a)

-   -   -   wherein            -   * represents the attachment point to the remainder of                the molecule;            -   Z¹ is selected from the group consisting of                CR^(Z1-1)R^(Z1-2), NR^(Z1-2), O, S, and                —CR^(Z1-1)═CR^(Z1-1)_,                -   wherein R^(Z1-1) is H or R¹⁴; and R^(Z1-2) is H or                    R¹⁴;            -   Z² is selected from the group consisting of                CR^(Z2-1)R^(Z2-2), NR^(Z2-2), O, S, and                —CR^(Z2-1)═CR^(Z2-1)—,                -   wherein R^(Z2-1) is H or R¹⁴; and R^(Z2-2) is H or                    R¹⁴;            -   Z³, independently at each occurrence, is C or N,                provided that at least one Z³ is C;            -   R¹³ is hydrogen or R¹⁴, or R¹³ and R^(Z1-2) are taken                together to form a double bond between the carbon atom                bearing R¹³ and Z¹, or R¹³ and R^(Z2-2) are taken                together to form a double bond between the carbon atom                bearing R¹³ and Z²; and            -   x1 is 1, 2, 3, or 4, and at least one R¹⁴ is halogen;

    -   R¹⁴ is selected, independently at each occurrence, from the        group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OH,        —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆ alkyl),        —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —NH(C₁-C₆        haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂,        —NR^(14-a)R^(14-b), —CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl),        —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),        —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆        haloalkyl)₂, —C(O)NR^(14-a)R^(14-b), —S(O)₂OH, —S(O)₂O(C₁-C₆        alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆        alkyl), —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,        —S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(14-a)R^(14-b), —OC(O)H,        —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H,        —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)C(O)H, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆        alkyl)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆        haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆        haloalkyl), —OS(O)₂(C₁-C₆ alkyl), —OS(O)₂(C₁-C₆ haloalkyl),        —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl),        —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆        haloalkyl)S(O)₂(C₁-C₆ haloalkyl);        -   wherein R^(14-a) and R^(14-b) are taken together with the            nitrogen atom which bears them to form a 3-10 membered            heterocycle;

    -   A² is C₆-C₁₀ aryl substituted by at least one halogen        substituent and optionally further substituted with one or more        R¹⁶ substituents, or 5-10 membered heteroaryl substituted by at        least one halogen substituent and optionally further substituted        with one or more R¹⁶ substituents;

    -   R¹⁶ is selected, independently at each occurrence, from the        group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OH,        —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆ alkyl),        —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —NH(C₁-C₆        haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂,        —NR^(16-a)R^(16-b), —CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl),        —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),        —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆        haloalkyl)₂, —C(O)NR^(16-a)R^(16-b), —S(O)₂OH, —S(O)₂O(C₁-C₆        alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆        alkyl), —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,        —S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(16-a)R^(16-b), —OC(O)H,        —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H,        —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)C(O)H, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆        alkyl)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆        haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆        haloalkyl), —OS(O)₂(C₁-C₆ alkyl), —OS(O)₂(C₁-C₆ haloalkyl),        —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl),        —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆        haloalkyl)S(O)₂(C₁-C₆ haloalkyl);        -   wherein R^(16-a) and R^(16-b) are taken together with the            nitrogen atom which bears them to form a 3-10 membered            heterocycle;

    -   R^(1a) and R^(1b) are independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, and halogen;

    -   R^(2a) and R^(2b) are independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, and halogen;

    -   when present, R^(3a) and R^(3b) are independently at each        occurrence selected from the group consisting of hydrogen, C₁-C₆        alkyl, and halogen;

    -   when present, R^(4a) and R^(4b) are independently at each        occurrence selected from the group consisting of hydrogen, C₁-C₆        alkyl, and halogen;

    -   or alternatively, R^(1a) and R^(2a) are taken together to form a        C₁-C₆ alkylene moiety;

    -   or alternatively, R^(1a) and an R^(3a) moiety, when present, are        taken together to form a C₁-C₆ alkylene moiety, and R^(1b) and        the R^(3b) in the geminal position to the R^(3a) taken together        with R^(1a), are both hydrogen;

    -   or alternatively, an R^(3a) moiety, when present, and an R^(4a)        moiety, when present, are taken together to form a C₁-C₆        alkylene moiety, and the R^(3b) in the geminal position to the        R^(3a) taken together with the R^(4a) moiety and the R^(4b) in        the geminal position to the R^(4a) taken together with the        R^(3a) moiety, are both hydrogen;

    -   R^(9a) and R^(9b) are taken together to form an oxo (═O)        substituent or an imido (═NH) substituent;

    -   R^(10a) is hydrogen; and

    -   R^(10b) is hydrogen.        Embodiment 2A. The compound of embodiment 1A, or a        pharmaceutically acceptable salt thereof, wherein x1 is 1 and        R¹⁴ is halogen.        Embodiment 3A. A compound of formula (1-3):

or a pharmaceutically acceptable salt thereof;wherein:

-   -   X² is CH or N;    -   R^(Y1) is hydrogen or C₁-C₆ alkyl;    -   Y² is selected from the group consisting of a bond, NR^(Y2), and        O; provided that when X² is N, then Y² is a bond;    -   R^(Y2) is hydrogen or C₁-C₆ alkyl;    -   r and s, independently of each other, are 0, 1, or 2;    -   A¹ is selected from the group consisting of:        -   a substituent of formula (A¹-a)

-   -   -   -   wherein                -   * represents the attachment point to the remainder                    of the molecule;                -   Z¹ is selected from the group consisting of                    CR^(Z1-1)R^(Z1-2), NR^(Z1-2), O, S, and                    —CR^(Z1-1)═CR^(Z1-1)—;                -    wherein R^(Z1-1) is H or R¹⁴; and R^(Z1-2) is H or                    R¹⁴;                -   Z² is selected from the group consisting of                    CR^(Z2-1)R^(Z2-2), NR^(Z2-2); O S, and                    —CR^(Z2-1)═CR^(Z2-1)—;                -    wherein R^(Z2-1) is H or R¹⁴; and R^(Z2-2) is H or                    R^(H);                -   Z³, independently at each occurrence, is C or N,                    provided that at least one Z³ is C;                -   R¹³ is hydrogen or R¹⁴, or R¹³ and R^(Z1-2) are                    taken together to form a double bond between the                    carbon atom bearing R¹³ and Z¹, or R¹³ and R^(Z2-2)                    are taken together to form a double bond between the                    carbon atom bearing R¹³ and Z²; and            -   x1 is 1, 2, 3, or 4, and at least one R¹⁴ is halogen;

    -   R¹⁴ is selected, independently at each occurrence, from the        group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OH,        —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆ alkyl),        —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —NH(C₁-C₆        haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂,        —NR^(14-a)R^(14-b), —CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl),        —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),        —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆        haloalkyl)₂, —C(O)NR^(14-a)R^(14-b), —S(O)₂OH, —S(O)₂O(C₁-C₆        alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆        alkyl), —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,        —S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(14-a)R^(14-b), —OC(O)H,        —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H,        —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)C(O)H, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆        alkyl)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆        haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆        haloalkyl), —OS(O)₂(C₁-C₆ alkyl), —OS(O)₂(C₁-C₆ haloalkyl),        —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl),        —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆        haloalkyl)S(O)₂(C₁-C₆ haloalkyl);        -   wherein R^(14-a) and R^(14-b) are taken together with the            nitrogen atom which bears them to form a 3-10 membered            heterocycle;

    -   A² is C₆-C₁₀ aryl substituted by at least one halogen        substituent and optionally further substituted with one or more        R¹⁶ substituents, or 5-10 membered heteroaryl substituted by at        least one halogen substituent and optionally further substituted        with one or more R¹⁶ substituents;

    -   R¹⁶ is selected, independently at each occurrence, from the        group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OH,        —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆ alkyl),        —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —NH(C₁-C₆        haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂,        —NR^(16-a)R^(16-b), —CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl),        —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),        —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆        haloalkyl)₂, —C(O)NR^(16-a)R^(16-b), —S(O)₂OH, —S(O)₂O(C₁-C₆        alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆        alkyl), —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,        —S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(16-a)R^(16-b), —OC(O)H,        —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H,        —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)C(O)H, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆        alkyl)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆        haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆        haloalkyl), —OS(O)₂(C₁-C₆ alkyl), —OS(O)₂(C₁-C₆ haloalkyl),        —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl),        —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆        haloalkyl)S(O)₂(C₁-C₆ haloalkyl);        -   wherein R^(16-a) and R^(16-b) are taken together with the            nitrogen atom which bears them to form a 3-10 membered            heterocycle;

    -   R^(1a) and R^(1b) are independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, and halogen;

    -   R^(2a) and R^(2b) are independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, and halogen;

    -   when present, R^(3a) and R^(3b) are independently at each        occurrence selected from the group consisting of hydrogen, C₁-C₆        alkyl, and halogen;

    -   when present, R^(4a) and R^(4b) are independently at each        occurrence selected from the group consisting of hydrogen, C₁-C₆        alkyl, and halogen;

    -   or alternatively, R^(1a) and R^(2a) are taken together to form a        C₁-C₆ alkylene moiety;

    -   or alternatively, R^(1a) and an R^(3a) moiety, when present, are        taken together to form a C₁-C₆ alkylene moiety, and R^(1b) and        the R^(3b) in the geminal position to the R^(3a) taken together        with R^(1a), are both hydrogen;

    -   or alternatively, an R^(3a) moiety, when present, and an R^(4a)        moiety, when present, are taken together to form a C₁-C₆        alkylene moiety, and the R^(3b) in the geminal position to the        R^(3a) taken together with the R^(4a) moiety and the R^(4b) in        the geminal position to the R^(4a) taken together with the        R^(3a) moiety, are both hydrogen;

    -   R^(9a) and R^(9b) are taken together to form an oxo (═O)        substituent or an imido (═NH) substituent, or alternatively,        R^(9a) and R^(9b) are both hydrogen;

    -   R^(10a) is selected from the group consisting of hydrogen,        —OR^(10a-a), and —NR^(10a-b)R^(10a-c);

    -   R^(10b) is hydrogen;

    -   R^(12a) and R^(12b) are taken together to form an oxo (═O)        substituent, or alternatively, R^(12a) and R^(12b) are both        hydrogen;

    -   R^(10a-a) is selected from the group consisting of hydrogen,        C₁-C₆ alkyl, and C₁-C₆ haloalkyl;

    -   or R^(10a-a) and R^(Y2) may be taken together to form a carbonyl        (C═O) moiety; and

    -   R^(10a-b) and R^(10a-c), independently of each other, are        selected from the group consisting of hydrogen, C₁-C₆ alkyl, and        C₁-C₆ haloalkyl.        Embodiment 4A. The compound of embodiment 3A, or a        pharmaceutically acceptable salt thereof, wherein x1 is 1 and        R¹⁴ is halogen.        Embodiment 5A. A compound of formula (2-3):

or a pharmaceutically acceptable salt thereof;wherein:

-   -   X¹ and X², independently of each other, are CH or N; provided        that at least one of X¹ and    -   X² is CH;    -   Y¹ is selected from the group consisting of a bond, NR^(Y1), and        O; provided that when X¹ is N, then Y¹ is a bond;    -   R^(Y1) is hydrogen or C₁-C₆ alkyl;    -   Y² is selected from the group consisting of a bond, NR^(Y2), and        O; provided that when X² is N, then Y² is a bond;    -   R^(Y2) is hydrogen or C₁-C₆ alkyl;    -   q1 is 1;    -   r and s, independently of each other, are 0, 1, or 2;    -   A¹ is C₆-C₁₀ aryl substituted by at least one halogen        substituent and optionally further substituted with one or more        R¹⁴ substituents, or 5-10 membered heteroaryl substituted by at        least one halogen substituent and optionally further substituted        with one or more R¹⁴ substituents; R¹⁴ is selected,        independently at each occurrence, from the group consisting of        halogen,    -   C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆        haloalkyl), —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,        —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)₂,        —N(C₁-C₆ haloalkyl)₂, —NR^(14-a)R^(14-b), —CN, —C(O)OH,        —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂,        —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆        alkyl)₂, —C(O)N(C₁-C₆ haloalkyl)₂, —C(O)NR^(14-a)R^(14-b),        —S(O)₂OH, —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),        —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ haloalkyl),        —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ haloalkyl)₂,        —S(O)₂NR^(14-a)R^(14-b), —OC(O)H, —OC(O)(C₁-C₆ alkyl),        —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl),        —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆        alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆ haloalkyl),        —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆ alkyl),        —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),        —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),        —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),        —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆        haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆        haloalkyl);        -   wherein R^(14-a) and R^(14-b) are taken together with the            nitrogen atom which bears them to form a 3-10 membered            heterocycle;    -   A² is C₆-C₁₀ aryl substituted by at least one halogen        substituent and optionally further substituted with one or more        R¹⁶ substituents, or 5-10 membered heteroaryl substituted by at        least one halogen substituent and optionally further substituted        with one or more R¹⁶ substituents;    -   R¹⁶ is selected, independently at each occurrence, from the        group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OH,        —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆ alkyl),        —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —NH(C₁-C₆        haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂,        —NR^(16-a)R^(16-b), —CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl),        —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),        —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆        haloalkyl)₂, —C(O)NR^(16-a)R^(16-b), —S(O)₂OH, —S(O)₂O(C₁-C₆        alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆        alkyl), —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,        —S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(16-a)R^(16-b), —OC(O)H,        —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H,        —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)C(O)H, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆        alkyl)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆        haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆        haloalkyl), —OS(O)₂(C₁-C₆ alkyl), —OS(O)₂(C₁-C₆ haloalkyl),        —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl),        —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆        haloalkyl)S(O)₂(C₁-C₆ haloalkyl);        -   wherein R^(16-a) and R^(16-b) are taken together with the            nitrogen atom which bears them to form a 3-10 membered            heterocycle;    -   R^(1a) and R^(1b) are independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, and halogen;    -   R^(2a) and R^(2b) are independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, and halogen;    -   when present, R^(3a) and R^(3b) are independently at each        occurrence selected from the group consisting of hydrogen, C₁-C₆        alkyl, and halogen;    -   when present, R^(4a) and R^(4b) are independently at each        occurrence selected from the group consisting of hydrogen, C₁-C₆        alkyl, and halogen;    -   or alternatively, R^(1a) and R^(2a) are taken together to form a        C₁-C₆ alkylene moiety;    -   or alternatively, R^(1a) and an R^(3a) moiety, when present, are        taken together to form a C₁-C₆ alkylene moiety, and R^(1b) and        the R^(3b) in the geminal position to the R^(3a) taken together        with R^(1a), are both hydrogen;    -   or alternatively, an R^(3a) moiety, when present, and an R^(4a)        moiety, when present, are taken together to form a C₁-C₆        alkylene moiety, and the R^(3b) in the geminal position to the        R^(3a) taken together with the R^(4a) moiety and the R^(4b) in        the geminal position to the R^(4a) taken together with the        R^(3a) moiety, are both hydrogen;    -   R^(5a) and R^(5b) are taken together to form an oxo (═O)        substituent or an imido (═NH) substituent;    -   R^(6a) is hydrogen;    -   R^(6b) is hydrogen;    -   R^(9a) and R^(9b) are taken together to form an oxo (═O)        substituent or an imido (═NH) substituent, or alternatively,        R^(9a) and R^(9b) are both hydrogen;    -   R^(10a) is selected from the group consisting of hydrogen,        —OR^(10a-a), and —NR^(10a-b)R^(10a-c);    -   R^(10b) is hydrogen;    -   R^(12a) and R^(12b) are taken together to form an oxo (═O)        substituent, or alternatively, R^(12a) and R^(12b) are both        hydrogen;    -   R^(10a-a) is selected from the group consisting of hydrogen,        C₁-C₆ alkyl, and C₁-C₆ haloalkyl;    -   or R^(10a-a) and R^(Y2) may be taken together to form a carbonyl        (C═O) moiety;    -   R^(10a-b) and R^(10a-c), independently of each other, are        selected from the group consisting of hydrogen, C₁-C₆ alkyl, and        C₁-C₆ haloalkyl; and    -   provided that when X² is N, then:    -   A¹ is C₆-C₁₀ aryl substituted by at least two halogen        substituents and optionally further substituted with one or more        R¹⁴ substituents, or 5-10 membered heteroaryl substituted by at        least two halogen substituents and optionally further        substituted with one or more R¹⁴ substituents; and    -   A² is C₆-C₁₀ aryl substituted by at least two halogen        substituents and optionally further substituted with one or more        R¹⁶ substituents, or 5-10 membered heteroaryl substituted by at        least two halogen substituents and optionally further        substituted with one or more R¹⁶ substituents.        Embodiment 6A. The compound of embodiment 5A, or a        pharmaceutically acceptable salt thereof, wherein X¹ is CH and        X² is CH.        Embodiment 7A. The compound of embodiment 5A, or a        pharmaceutically acceptable salt thereof, wherein X¹ is N and X²        is CH.        Embodiment 8A. The compound of embodiment 5A, or a        pharmaceutically acceptable salt thereof, wherein:    -   X¹ is CH;    -   X² is N;    -   A¹ is C₆-C₁₀ aryl substituted by at least two halogen        substituents and optionally further substituted with one or more        R¹⁴ substituents, or 5-10 membered heteroaryl substituted by at        least two halogen substituents and optionally further        substituted with one or more R¹⁴ substituents; and    -   A² is C₆-C₁₀ aryl substituted by at least two halogen        substituents and optionally further substituted with one or more        R¹⁶ substituents, or 5-10 membered heteroaryl substituted by at        least two halogen substituents and optionally further        substituted with one or more R¹⁶ substituents.        Embodiment 9A. A compound of formula (XX):

or a pharmaceutically acceptable salt thereof;wherein:

-   -   X⁵ is CH or N;    -   Y⁵ is selected from the group consisting of a bond, NR^(Y5), and        O; provided that when X⁵ is N, then Y⁵ is a bond;    -   R^(Y5) is hydrogen or C₁-C₆ alkyl;    -   R^(N) is hydrogen or C₁-C₆ alkyl;    -   m⁴, n⁵, p³, and q⁴, independently of each other, are 0 or 1;    -   r3 and s3, independently of each other, are 0, 1, or 2;    -   A¹³ is selected from the group consisting of:        -   C₆-C₁₀ aryl optionally substituted with one or more R⁹⁵            substituents; and        -   5-10 membered heteroaryl optionally substituted with one or            more R⁹⁵ substituents;    -   R⁹⁵ is selected, independently at each occurrence, from the        group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OH,        —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆ alkyl),        —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —NH(C₁-C₆        haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂,        —NR^(95-a)R^(95-b), —CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl),        —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),        —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆        haloalkyl)₂, —C(O)NR^(95-a)R^(95-b), —S(O)₂OH, —S(O)₂O(C₁-C₆        alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆        alkyl), —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,        —S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(95-a)R^(95-b), —OC(O)H,        —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H,        —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)C(O)H, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆        alkyl)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆        haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆        haloalkyl), —OS(O)₂(C₁-C₆ alkyl), —OS(O)₂(C₁-C₆ haloalkyl),        —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl),        —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆        haloalkyl)S(O)₂(C₁-C₆ haloalkyl);        -   wherein R^(95-a) and R^(95-b) are taken together with the            nitrogen atom which bears them to form a 3-10 membered            heterocycle;    -   R^(84a) and R^(84b) are independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, and halogen;    -   R^(85a) and R^(85b) are independently selected from the group        consisting of hydrogen, C₁-C₆ alkyl, and halogen;    -   when present, R^(86a) and R^(86b) are independently at each        occurrence selected from the group consisting of hydrogen, C₁-C₆        alkyl, and halogen;    -   when present, R^(87a) and R^(87b) are independently at each        occurrence selected from the group consisting of hydrogen, C₁-C₆        alkyl, and halogen;    -   or, R^(84a) and R^(85a) are taken together to form a C₁-C₆        alkylene moiety;    -   or, R^(84a) and an R^(86a) moiety, when present, are taken        together to form a C₁-C₆ alkylene moiety;    -   or, an R^(86a) moiety, when present, and an R^(87a) moiety, when        present, are taken together to form a C₁-C₆ alkylene moiety;    -   R⁸⁸ is selected from the group consisting of hydrogen, C₁-C₆        alkyl, C₁-C₆ haloalkyl, —C(O)(C₁-C₆ alkyl), —C(O)(C₁-C₆        haloalkyl), —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆        haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆        haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆ haloalkyl)₂,        —C(O)NR^(88-a)R^(88-b), —S(O)₂OH, —S(O)₂O(C₁-C₆ alkyl),        —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl),        —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆        haloalkyl)₂, and —S(O)₂NR^(88-a)R^(88-b);        -   wherein R^(88-a) and R^(88-b) are taken together with the            nitrogen atom which bears them to form a 3-10 membered            heterocycle;    -   R⁸⁹ is selected, independently at each occurrence, from the        group consisting of hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆        haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH,        —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl),        —NH(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂,        —NR^(89-a)R^(89-b), —CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl),        —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),        —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆        haloalkyl)₂, —C(O)NR^(89-a)R^(89-b), —S(O)₂OH, —S(O)₂O(C₁-C₆        alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆        alkyl), —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,        —S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(89-a)R^(89-b), —OC(O)H,        —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H,        —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)C(O)H, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆        alkyl)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆        haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆        haloalkyl), —OS(O)₂(C₁-C₆ alkyl), —OS(O)₂(C₁-C₆ haloalkyl),        —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆        alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl),        —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆        haloalkyl)S(O)₂(C₁-C₆ haloalkyl);    -   wherein R^(89-a) and R^(89-b) are taken together with the        nitrogen atom which bears them to form a 3-10 membered        heterocycle;    -   when present, R^(90a) and R^(90b) are taken together to form an        oxo (═O) substituent or an imido (═NH) substituent, or        alternatively, R^(90a) and R^(90b) are both hydrogen;    -   when present, R^(91a) is selected from the group consisting of        hydrogen, —OR^(91a-a), and NR^(91a-b)R^(91a-c);    -   when present, R^(91b) is hydrogen;    -   or alternatively, R^(91a) and R^(91b) are taken together to form        a moiety selected from the group consisting of —O—CH₂—CH₂—,        —CH₂—O—CH₂—, —CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—, —CH₂—O—CH₂—CH₂—,        —CH₂—CH₂—O—CH₂—, —CH₂—CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—CH₂—,        —CH₂—O—CH₂—CH₂—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—CH₂—CH₂—O—CH₂—,        and —CH₂—CH₂—CH₂—CH₂—O—;    -   when present, R^(92a) and R^(92b) are both hydrogen;    -   when present, R^(93a) and R^(93b) are taken together to form an        oxo (═O) substituent, or alternatively, R^(93a) and R^(93b) are        both hydrogen;    -   R^(91a-a) is selected from the group consisting of hydrogen,        C₁-C₆ alkyl, and C₁-C₆ haloalkyl;    -   or R^(91a-a) and R^(Y5) may be taken together to form a carbonyl        (C═O) moiety; and    -   R^(91a-b) and R^(91a-c), independently of each other, are        selected from the group consisting of hydrogen, C₁-C₆ alkyl, and        C₁-C₆ haloalkyl;    -   provided that when m⁴ is 0, n⁵ is 0, and q⁴ is 0, then p³ is 1        and A¹³ is a substituent of formula (A¹³-a)

-   -   -   wherein            -   * represents the attachment point to the remainder of                the molecule;            -   Z¹⁴ is selected from the group consisting of                CR^(Z14-1)R^(Z14-2), NR^(Z14-2),                C(R^(Z14-1)R^(Z14-2))N(R^(Z14-2)), O,                C(R^(Z14-1)R^(Z14-2))O, S, C(R^(Z14-1)R^(Z14-2))s, and                —CR^(Z14-1)═CR^(Z14-1)—;                -   wherein R^(Z14-1) is hydrogen or R¹⁶; and R^(Z14-2)                    is hydrogen or R⁹⁵;            -   Z¹⁵ is selected from the group consisting of                CR^(Z15-1)R^(Z15-2), NR^(Z15-2),                C(R^(Z15-1)R^(Z15-2))N(R^(Z15-2)), O,                C(R^(Z15-1)R^(Z15-2))O, S, C(R^(Z15-1)R^(Z15-2))S, and                —CR^(Z15-1)═CR^(Z15-1)—;                -   wherein R^(Z15-1) is hydrogen or R⁹⁵; and R^(Z15-2)                    is hydrogen or R⁹⁵;            -   Z¹⁶, independently at each occurrence, is CH, CR⁹⁵, or                N;            -   R⁹⁴ is hydrogen or R⁹⁵, or R⁹⁴ and R^(Z14-2) are taken                together to form a double bond between the carbon atom                bearing R⁹⁴ and Z¹⁴, or R⁹⁴ and R^(Z15-2) are taken                together to form a double bond between the carbon atom                bearing R⁹⁴ and Z¹⁵; and            -   x23 is 0, 1, 2, 3, or 4.                Embodiment 10A. The compound of embodiment 9A, wherein                the compound of formula (XX) is a compound of formula                (XX-I):

or a pharmaceutically acceptable salt thereof.Embodiment 11A. The compound of embodiment 10A, wherein the compound offormula (XX-I) is a compound of formula (XX-I-1):

or a pharmaceutically acceptable salt thereof;

-   -   wherein R^(N), R^(Y5), R⁸⁸, R⁸⁹, R^(93a), and R^(93b) are as        defined in the compounds of formula (XX), and wherein A¹³ is a        substituent of formula (A¹³-a)

-   -   -   wherein            -   * represents the attachment point to the remainder of                the molecule;            -   Z¹⁴ is selected from the group consisting of                CR^(Z14-1)R^(Z14-2), NR^(Z14-2),                C(R^(Z14-1)R^(Z14-2))N(R^(Z14-2)), O,                C(R^(Z14-1)R^(Z14-2))O, s, C(R^(Z14-1)R^(Z14-2))S, and                —CR^(Z14-1)═CR^(Z14-1)—;                -   wherein R^(Z14-1) is hydrogen or R¹⁶; and R^(Z14-2)                    is hydrogen or R⁹⁵;            -   Z¹⁵ is selected from the group consisting of                CR^(Z15-1)R^(Z15-2), NR^(Z15-2),                C(R^(Z15-1)R^(Z15-2))N(R^(Z15-2)), O,                C(R^(Z15-1)R^(Z15-2))O, S, C(R^(Z15-1)R^(Z15-2))S, and                —CR^(Z15-1)═CR^(Z15-1)—;                -   wherein R^(Z15-1) is hydrogen or R⁹⁵; and R^(Z15-2)                    is hydrogen or R⁹⁵;            -   Z¹⁶, independently at each occurrence, is CH, CR⁹⁵, or                N;            -   R⁹⁴ is hydrogen or R⁹⁵, or R⁹⁴ and R^(Z14-2) are taken                together to form a double bond between the carbon atom                bearing R⁹⁴ and Z¹⁴, or R⁹⁴ and R^(Z15-2) are taken                together to form a double bond between the carbon atom                bearing R⁹⁴ and Z¹⁵;            -   x23 is 0, 1, 2, 3, or 4; and            -   R⁹⁵ is selected, independently at each occurrence, from                the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆                haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl),                —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂,                —NH(C₁-C₆ alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆                alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(95-a)R^(95-b), —CN,                —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),                —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆                haloalkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆                haloalkyl)₂, —C(O)NR^(95-a)R^(95-b), —S(O)₂OH,                —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl),                —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆                haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆                haloalkyl)₂, —S(O)₂NR^(95-a)R^(95-b), —OC(O)H,                —OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl),                —N(H)C(O)H, —N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ alkyl)C(O)H, —N(C₁-C₆                alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆                haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆                haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),                —OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl),                —N(H)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆                alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ alkyl), and —N(C₁-C₆                haloalkyl)S(O)₂(C₁-C₆ haloalkyl).                Embodiment 12A. The compound of embodiment 10A, wherein                the compound of formula (XX-I) is a compound of formula                (XX-I-2):

or a pharmaceutically acceptable salt thereof.Embodiment 13A. The compound of embodiment 10A, wherein the compound offormula (XX-I) is a compound of formula (XX-I-2b):

or a pharmaceutically acceptable salt thereof.Embodiment 14A. The compound of embodiment 10A, wherein the compound offormula (XX-I) is a compound of formula (XX-I-3):

or a pharmaceutically acceptable salt thereof.Embodiment 15A. The compound of embodiment 9A, wherein the compound offormula (XX) is a compound of formula (XX-II):

or a pharmaceutically acceptable salt thereof.Embodiment 16A. The compound of embodiment 15A, wherein the compound offormula (XX-II) is a compound of formula (XX-II-3):

or a pharmaceutically acceptable salt thereof.Embodiment 17A. A compound selected from the group consisting of acompound of Table 1, or a pharmaceutically acceptable salt thereof.Embodiment 18A. A pharmaceutical composition comprising a compound ofany of the preceding embodiments, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.Embodiment 19A. A method of treating a disease or disorder mediated byan integrated stress response (ISR) pathway in an individual in needthereof comprising administering to the individual a therapeuticallyeffective amount of a compound of any one of embodiments 1A to 17A, or apharmaceutically acceptable salt thereof, or a therapeutically effectiveamount of a pharmaceutical composition of embodiment 18A.Embodiment 20A. The method of embodiment 19A, wherein the compound, thepharmaceutically acceptable salt, or the pharmaceutical composition isadministered in combination with a therapeutically effective amount ofone or more additional anti-cancer agents.Embodiment 21A. The method of embodiment 19A, wherein the disease ordisorder is mediated by phosphorylation of eIF2α and/or the guaninenucleotide exchange factor (GEF) activity of eIF2B.Embodiment 22A. The method of any one of embodiments 19A-21A, whereinthe disease or disorder is mediated by a decrease in protein synthesis.Embodiment 23A. The method of any one of embodiments 19A-22A, whereinthe disease or disorder is mediated by the expression of ATF4, CHOP orBACE-1.Embodiment 24A. The method of any of embodiments 19A-23A, wherein thedisease or disorder is a neurodegenerative disease, an inflammatorydisease, an autoimmune disease, a metabolic syndrome, a cancer, avascular disease, an ocular disease, a musculoskeletal disease, or agenetic disorder.Embodiment 25A. The method of embodiment 24A, wherein the disease isvanishing white matter disease, childhood ataxia with CNShypomyelination, intellectual disability syndrome, Alzheimer's disease,prion disease, Creutzfeldt-Jakob disease, Parkinson's disease,amyotrophic lateral sclerosis (ALS) disease, cognitive impairment,frontotemporal dementia (FTD), traumatic brain injury, postoperativecognitive dysfunction (PCD), neuro-otological syndromes, hearing loss,Huntington's disease, stroke, chronic traumatic encephalopathy, spinalcord injury, dementias or cognitive impairment, arthritis, psoriaticarthritis, psoriasis, juvenile idiopathic arthritis, asthma, allergicasthma, bronchial asthma, tuberculosis, chronic airway disorder, cysticfibrosis, glomerulonephritis, membranous nephropathy, sarcoidosis,vasculitis, ichthyosis, transplant rejection, interstitial cystitis,atopic dermatitis or inflammatory bowel disease, Crohn's disease,ulcerative colitis, celiac disease, systemic lupus erythematosus, type 1diabetes, multiple sclerosis, rheumatoid arthritis, alcoholic liversteatosis, obesity, glucose intolerance, insulin resistance,hyperglycemia, fatty liver, dyslipidemia, hyperlipidemia, type 2diabetes, pancreatic cancer, breast cancer, kidney cancer, bladdercancer, prostate cancer, testicular cancer, urothelial cancer,endometrial cancer, ovarian cancer, cervical cancer, renal cancer,esophageal cancer, gastrointestinal stromal tumor (GIST), multiplemyeloma, cancer of secretory cells, thyroid cancer, gastrointestinalcarcinoma, chronic myeloid leukemia, hepatocellular carcinoma, coloncancer, melanoma, malignant glioma, glioblastoma, glioblastomamultiforme, astrocytoma, dysplastic gangliocytoma of the cerebellum,Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, ductaladenocarcinoma, adenosquamous carcinoma, nephroblastoma, acinar cellcarcinoma, lung cancer, non-Hodgkin's lymphoma, Burkitt's lymphoma,chronic lymphocytic leukemia, monoclonal gammopathy of undeterminedsignificance (MGUS), plasmocytoma, lymphoplasmacytic lymphoma, acutelymphoblastic leukemia, Pelizaeus-Merzbacher disease, atherosclerosis,abdominal aortic aneurism, carotid artery disease, deep vein thrombosis,Buerger's disease, chronic venous hypertension, vascular calcification,telangiectasia or lymphoedema, glaucoma, age-related maculardegeneration, inflammatory retinal disease, retinal vascular disease,diabetic retinopathy, uveitis, rosacea, Sjogren's syndrome orneovascularization in proliferative retinopathy, hyperhomocysteinemia,skeletal muscle atrophy, myopathy, muscular dystrophy, muscular wasting,sarcopenia, Duchenne muscular dystrophy (DMD), Becker's disease,myotonic dystrophy, X-linked dilated cardiomyopathy, spinal muscularatrophy (SMA), Down syndrome, MEHMO syndrome, metaphysealchondrodysplasia, Schmid type (MCDS), depression, or social behaviorimpairment.Embodiment 26A. A method of producing a protein, comprising contacting aeukaryotic cell comprising a nucleic acid encoding the protein with thecompound or salt of any one of embodiments 1A-17A.Embodiment 27A. The method of embodiment 26A, comprising culturing thecell in an in vitro culture medium comprising the compound or salt.Embodiment 28A. A method of culturing a eukaryotic cell comprising anucleic acid encoding a protein, comprising contacting the eukaryoticcell with an in vitro culture medium comprising a compound or salt ofany one of embodiments 1-17A.Embodiment 29A. The method of any one of embodiments 26A-28A, whereinthe nucleic acid encoding the protein is a recombinant nucleic acid.Embodiment 30A. The method of any one of embodiments 26A-29A, whereinthe cell is a human embryonic kidney (HEK) cell or a Chinese hamsterovary (CHO) cell.Embodiment 31A. The method of any one of embodiments 26A-29A, whereinthe cell is a yeast cell, a wheat germ cell, an insect cell, a rabbitreticulocyte, a cervical cancer cell, a baby hamster kidney cell, amurine myeloma cell, an HT-1080 cell, a PER.C6 cell, a plant cell, ahybridoma cell, or a human blood derived leukocyteEmbodiment 32A. A method of producing a protein, comprising contacting acell-free protein synthesis (CFPS) system comprising eukaryoticinitiation factor 2 (eIF2) and a nucleic acid encoding a protein withthe compound or salt of any one of embodiments 1A-17A.Embodiment 33A. The method of any one of embodiments 26A-32A, whereinthe protein is an antibody or a fragment thereof.Embodiment 34A. The method of any one of embodiments 26A-32A, whereinthe protein is a recombinant protein, an enzyme, an allergenic peptide,a cytokine, a peptide, a hormone, erythropoietin (EPO), an interferon, agranulocyte-colony stimulating factor (G-CSF), an anticoagulant, or aclotting factor.Embodiment 35A. The method of any one of embodiments 26A-34A, comprisingpurifying the protein.Embodiment 36A. An in vitro cell culture medium, comprising the compoundor salt of any one of embodiments 1A-17A and nutrients for cellulargrowth.Embodiment 37A. The cell culture medium of embodiment 36A, comprising aeukaryotic cell comprising a nucleic acid encoding a protein.Embodiment 38. The cell culture medium of embodiment 36A or 37A, furthercomprising a compound for inducing protein expression.Embodiment 39A. The cell culture medium of any one of embodiments36A-38A, wherein the nucleic acid encoding the protein is a recombinantnucleic acid.Embodiment 40A. The cell culture medium of any one of embodiments36A-39A, wherein the protein is an antibody or a fragment thereof.Embodiment 41A. The cell culture medium of any one of embodiments36A-39A, wherein the protein is a recombinant protein, an enzyme, anallergenic peptide, a cytokine, a peptide, a hormone, erythropoietin(EPO), an interferon, a granulocyte-colony stimulating factor (G-CSF),an anticoagulant, or a clotting factor.Embodiment 42A. The cell culture medium of any one of embodiments36A-41A, wherein the eukaryotic cell is a human embryonic kidney (HEK)cell or a Chinese hamster ovary (CHO) cell.Embodiment 43A. The cell culture medium of any one of embodiments36A-41A, wherein the cell is a yeast cell, a wheat germ cell, an insectcell, a rabbit reticulocyte, a cervical cancer cell, a baby hamsterkidney cell, a murine myeloma cell, an HT-1080 cell, a PER.C6 cell, aplant cell, a hybridoma cell, or a human blood derived leukocyteEmbodiment 44A. A cell-free protein synthesis (CFPS) system comprisingeukaryotic initiation factor 2 (eIF2) and a nucleic acid encoding aprotein with the compound or salt of any one of embodiments 1A-17A.Embodiment 45A. The CFPS system of embodiment 40A, comprising aeukaryotic cell extract comprising eIF2.Embodiment 46A. The CFPS system of embodiment 44A or 45A, furthercomprising eIF2B.Embodiment 47A. The CFPS system of any one of embodiments 44A-46A,wherein the protein is an antibody or a fragment thereof.Embodiment 48A. The CFPS system of any one of embodiments 44A-47A,wherein the protein is a recombinant protein, an enzyme, an allergenicpeptide, a cytokine, a peptide, a hormone, erythropoietin (EPO), aninterferon, a granulocyte-colony stimulating factor (G-CSF), ananticoagulant, or a clotting factor.

EXAMPLES

Although the invention has been described and illustrated with a certaindegree of particularity, it is understood that the present disclosurehas been made only by way of example, and that numerous changes in thecombination and arrangement of parts can be resorted to by those skilledin the art without departing from the spirit and scope of the invention,as defined by the claims.

The chemical reactions in the Examples described can be readily adaptedto prepare a number of other compounds disclosed herein, and alternativemethods for preparing the compounds of this disclosure are deemed to bewithin the scope of this disclosure. For example, the synthesis ofnon-exemplified compounds according to the present disclosure can besuccessfully performed by modifications apparent to those skilled in theart, e.g., by appropriately protecting interfering groups, by utilizingother suitable reagents known in the art other than those described, orby making routine modifications of reaction conditions, reagents, andstarting materials. Alternatively, other reactions disclosed herein orknown in the art will be recognized as having applicability forpreparing other compounds of the present disclosure.

In some cases, stereoisomers are separated to give single enantiomers ordiastereomers as single, unknown stereoisomers, and are arbitrarilydrawn as single isomers. Where appropriate, information is given onseparation method and elution time and order. In the biologicalexamples, compounds tested were prepared in accordance to the syntheticprocedures described therein. For any given compound of unknown absolutestereochemistry for which specific rotation is available, biologicaldata for that compound was obtained using the enantiomer ordiastereoisomer associated with said specific rotation.

In some cases, optical rotation was determined on Jasco DIP-360 digitalpolarimeter at a wavelength of 589 nm (sodium D line) and are reportedas [α]_(D) ^(T) for a given temperature T (expressed in ° C.). Whereappropriate, information is given on solvent and concentration(expressed as g/100 mL).

Abbreviations:

br. s. Broad singlet

chloroform-d Deuterated chloroform

methanol-d₄ Deuterated methanol

DIAD Diisopropyl azodicarboxylate

DCM Dichloromethane

DEA Diethylamine

DIPEA Diisopropylethylamine

DMF N,N-Dimethylformamide

DMSO-d₆ Deuterated dimethylsulfoxide

d Doublet

EDC.HCl 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloric acid

EtOAc Ethyl acetate

EtOH Ethanol

g Gram

HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate)

HOBT Hydroxybenzotriazole

HPLC High Performance Liquid Chromatography

L Litre

LCMS Liquid Chromatography Mass Spectrometry

MeCN Acetonitrile

MeOH Methanol

mg Milligram

mL Millilitre

mmol Millimoles

m multiplet

NMR Nuclear Magnetic Resonance

iPrOH Isopropanol

q quartet

RT Room temperature

s singlet

SFC Supercritical Fluid Chromatography

TFA trifluoroacetic acid

THF Tetrahydrofuran

TLC Thin layer chromatography

t triplet

EXAMPLES Example 1 Synthesis oftrans-2-(4-chlorophenoxy)-N-(4-((3-(4-chlorophenoxy)-2-hydroxypropyl)amino)cyclohexyl)acetamide

To a stirred solution oftrans-N-(4-aminocyclohexyl)-2-(4-chlorophenoxy)acetamidotrifluoroacetate salt (100 mg, 0.252 mmol, 1 equiv) in MeCN (10 mL), wasadded 2-((4-chlorophenoxy)methyl)oxirane (84 mg, 0.454 mmol, 1.8 equiv)and K₂CO₃ (70 mg, 0.504 mmol, 2 equiv) at RT. The reaction mixture wasstirred overnight at 90° C. Progress of the reaction was monitored byTLC and LCMS. After completion of the reaction, the reaction mixture wasdiluted with water (30 mL) and extracted with EtOAc (100 mL×2). Theorganic layer was washed with water (50 mL) and brine solution (50 mL).Organic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure to obtain crude compound, which was purified byreverse phase HPLC to obtaintrans-2-(4-chlorophenoxy)-N-(4-((3-(4-chlorophenoxy)2-hydroxypropyl)amino)cyclohexyl)acetamide(Compound 1-6 mg, 5%) as an off white solid compound. LCMS: 467 [M+H]⁺;¹HNMR (400 MHz, DMSO-d₆) δ 8.26 (s, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.33(t, J=8.2 Hz, 4H), 6.96 (d, J=8.5 Hz, 4H), 4.44 (s, 2H), 3.91 (dq,J=29.5, 6.4, 5.7 Hz, 3H), 3.57 (d, J=11.4 Hz, 2H), 2.81-2.72 (m, 2H),1.95-1.85 (m, 2H), 1.75 (dd, J=11.9, 4.6 Hz, 2H), 1.35-1.21 (m, 3H),1.13 (t, J=12.6 Hz, 2H).

Example 2 Synthesis oftrans-2-(4-chloro-3-fluorophenoxy)-N-(4-((3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)amino)cyclohexyl)acetamide

Step 1 Synthesis of 2-(4-chloro-3-fluorophenoxy)acetic acid:

To a stirred mixture of 4-chloro-3-fluorophenol (1 g, 0.068 mol, 1equiv) and 2-chloroacetic acid (2.5 g, 0.273 mol, 4 equiv) in water (20mL), was added NaOH (1.08 g, 0.273 mol, 4 equiv) and the reactionmixture was heated at 100° C. overnight. The reaction was monitored byTLC and LCMS. After completion of the reaction, the reaction mixture wasneutralized by using 3N HCl (20 mL). The resultant solid was filteredoff and residue was washed with water and dried under vacuum to obtain2-(4-chloro-3-fluorophenoxy)acetic acid (700 mg, 51%) as white solid.LCMS: 204 [M+H]⁺.

Step 2 Synthesis of trans-tert-butyl(4-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclohexyl)carbamate:

To a stirred mixture of 2-(4-Chloro-3-fluorophenoxy)acetic acid (500 mg,2.43 mmol, 1 equiv) in DMF (5 mL), was added DIPEA (1.6 mL, 9.76 mmol, 4equiv), HOBT (540 mg, 3.18 mmol, 1.5 equiv) and EDC.HCl (702 mg, 3.66mmol, 1.5 equiv). The reaction mixture was stirred at RT for 30 min andthen trans-tert-butyl 4-aminocyclohexylcarbamate (838 mg, 9.76 mmol, 4equiv) was added. The resultant reaction mixture was stirred at RTovernight. The reaction was monitored by LCMS. After completion of thereaction, the reaction mixture was filtered off and the residue waswashed with water and dried under vacuum to obtain trans-tert-butyl(4-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclohexyl)carbamate (170 mg,18%) as white solid. LCMS: 399 [M+1-1]⁺.

Step 3 Synthesis oftrans-N-(4-aminocyclohexyl)-2-(4-chloro-3-fluorophenoxy)acetamidetrifluoroacetate salt:

To a stirred solution of trans-tert-butyl(4-(2-(4-chloro-3-fluorophenoxy)acetamido) cyclohexyl)carbamate (150 mg,0.395 mmol, 1 equiv) in DCM (5 mL) was added trifluoroacetic acid (3 mL)and the resultant reaction mixture was stirred at RT for 1 hr undernitrogen atmosphere. The reaction was monitored by TLC and LCMS. Aftercompletion of reaction, the reaction mixture was concentrated underreduced pressure to obtain a sticky crude compound which was trituratedwith hexane (10 mL) and diethyl ether and dried under vacuum to obtaintrans-N-(4-aminocyclohexyl)-2-(4-chloro-3-fluorophenoxy)acetamidetrifluoroacetate salt (100 mg, 89%) as brown solid. LCMS: 300 [M+14]⁺.

Step 4 Synthesis oftrans-2-(4-chloro-3-fluorophenoxy)-N-(4-((3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)amino)cyclohexyl)acetamide:

To a stirred solution oftrans-N-(4-aminocyclohexyl)-2-(4-chloro-3-fluorophenoxy)acetamidetrifluoroacetate salt (100 mg, 0.24 mmol, 1 equiv), and2-((4-chloro-3-fluorophenoxy)methyl)oxirane (67 mg, 0.338 mmol, 1.4equiv) in MeCN (5 mL), was added K₂CO₃ (99 mg, 0.72 mmol, 3 equiv). Theresultant reaction mixture was heated at 90° C. overnight. The reactionwas monitored by TLC and LCMS. After completion of the reaction, thereaction mixture was diluted with water (30 mL) and extracted with EtOAc(2×50 mL) and washed with water (2×20 mL), brine solution (2×20 mL),dried over anhydrous sodium sulfate and concentrated under reducedpressure to obtain a crude mixture which was purified by reversed-phaseHPLC to obtaintrans-2-(4-chloro-3-fluorophenoxy)-N-(4-((3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)amino)cyclohexyl)acetamide(Compound 2-7 mg, 4%) as light greenish solid. LCMS: 503 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 7.92 (d, J=6.36 Hz, 2H), 7.37-7.57 (m, 2H), 7.06(d, J=11.74 Hz, 2H), 6.83 (m, 2H), 4.48 (s, 4H), 3.97 (m., 1H), 3.89 (d,J=6.85 Hz, 1H), 3.80 (m, 1H), 3.55 (m, 3H), 1.85 (m, 1H), 1.77 (d,J=14.18 Hz, 3H), 1.35 (br. s., 1H), 1.23 (br. s., 2H).

Example 3 Synthesis of2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)-2-hydroxypropyl)piperidin-4-yl)acetamide

Step 1 Synthesis of tert-butyl(1-(3-(4-chlorophenoxy)-2-hydroxypropyl)piperidin-4-yl)carbamate:

To a stirred solution of tert-butyl piperidin-4-ylcarbamate (0.500 g,2.500 mmol, 1.0 equiv) in DMF (5 mL) was added2-((4-chlorophenoxy)methyl)oxirane (0.460 g, 2.500 mmol, 2.0 equiv) atRT. The resulting reaction mixture was heated at 100° C. for 12 hr.Progress of the reaction was monitored by ¹H NMR. Reaction was quenchedby adding water and the resulting precipitate was filtered off. Theobtained solid was washed with water (25 mL×2) and dried under vacuum toobtain tert-butyl(1-(3-(4-chlorophenoxy)-2-hydroxypropyl)piperidin-4-yl)carbamate (0.700g, 73% Yield) as a white solid. LCMS 386.3 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ 7.26-7.38 (m, J=8.77 Hz, 2H), 6.89-7.01 (m, J=8.77 Hz, 2H),6.74 (d, J=7.45 Hz, 1H), 4.84 (d, J=4.38 Hz, 1H), 3.82-3.99 (m, 3H),3.17 (d, J=5.26 Hz, 1H), 2.75-2.92 (m, 2H), 2.25-2.41 (m, 2H), 1.91-2.07(m, 2H), 1.65 (d, J=10.52 Hz, 2H), 1.37 (s, 9H).

Step 2 Synthesis of1-(4-aminopiperidin-1-yl)-3-(4-chlorophenoxy)propan-2-oltrifluoroacetate salt:

To a stirred solution of tert-butyl(1-(3-(4-chlorophenoxy)-2-hydroxypropyl)piperidin-4-yl)carbamate (0.700g, 21.822 mmol, 1.0 equiv) in DCM (30 mL) was added trifluoroacetic acid(5 mL) at RT. The reaction mixture was allowed to stir at RT overnight.DCM and excess of trifluoroacetic acid were removed under reducedpressure to obtain1-(4-aminopiperidin-1-yl)-3-(4-chlorophenoxy)propan-2-oltrifluoroacetate salt (0.800 g, 100% Yield) as an oil. ¹HNMR (400 MHz,DMSO-d₆) δ 9.61 (br. s., 1H), 8.18 (br. s., 2H), 7.27-7.45 (m, J=9.21Hz, 2H), 6.92-7.04 (m, J=8.77 Hz, 2H), 4.24-4.33 (m, 1H), 3.62 (d,J=10.96 Hz, 2H), 3.04-3.33 (m, 5H), 2.01-2.20 (m, 2H), 1.86-1.96 (m,1H), 1.78 (d, J=13.15 Hz, 1H).

Step 3 Synthesis of2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)-2-hydroxypropyl)piperidin-4-yl)acetamide:

To a solution of1-(4-aminopiperidin-1-yl)-3-(4-chlorophenoxy)propan-2-oltrifluoroacetate salt (0.700 g, 1.758 mmol, 1.0 equiv) in DMF (10 mL)was added 2-(4-chlorophenoxy)acetic acid (0.396 g, 1.934 mmol, 1.1equiv) and HATU (1.340 g, 3.517 mmol, 2.0 equiv) at RT. The reactionmixture was stirred for 10 minutes and then DIPEA (1.6 mL, 8.793 mmol,5.0 equiv) was added. The resultant reaction mixture was allowed to stirat RT overnight. Progress of the reaction was monitored by LCMS. Thereaction mixture was diluted with water (50 mL) and extracted with EtOAc(100 mL×2). The combined organic layer was washed with water (50 mL×4),dried over anhydrous sodium sulfate and concentrated under reducedpressure to obtain the crude compound which was purified by reversephase HPLC to obtain2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)-2-hydroxypropyl)piperidin-4-yl)acetamide(Compound 5-0.550 g, 70% Yield) as an off-white solid. LCMS: 453.1[M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 8.09-8.16 (m, 1H), 7.34 (d, J=8.77Hz, 2H), 6.90-7.01 (m, 2H), 5.59 (br. s., 1H), 4.48 (s, 2H), 4.14 (br.s., 1H), 3.94 (dq, J=4.60, 10.01 Hz, 1H), 3.78 (br. s., 1H), 2.90 (br.s., 2H), 1.82 (d, J=10.09 Hz, 1H), 1.58-1.75 (m, 1H).

Example 4 Synthesis oftrans-3-(4-chlorophenoxy)-N-(4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-2-hydroxypropanamide

Step 1 Synthesis oftrans-N-(4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)oxirane-2-carboxamide:

To a stirred mixture oftrans-N-(4-aminocyclohexyl)-2-(4-chlorophenoxy)acetamide (300 mg, 1.063mmol, 1 equiv) in DMF (15 mL), was added triethylamine (0.5 mL, 4.252mmol, 4 equiv), HOBT (144 mg, 1.595 mmol, 1.5 equiv) and EDC.HCl (305mg, 1.595 mmol, 1.5 equiv). The reaction mixture was stirred at RT for30 min. Oxirane-2-carboxylic acid (140 mg, 1.595 mmol, 1.5 equiv) wasthen added. The resultant reaction mixture was stirred at RT overnight.Progress of the reaction was monitored by LCMS. After completion of thereaction, water (50 mL) was added and extracted with EtOAc (50 mL×2).The combined organic layer was washed with water (30 mL), brine solution(2×30 mL), dried over anhydrous sodium sulfate and concentrated underreduced pressure to obtaintrans-N-(4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)oxirane-2-carboxamide(300 mg) as a white solid which was taken for the next step without anyfurther purification. LCMS: 353 [M+H]⁺.

Step 2 Synthesis oftrans-3-(4-chlorophenoxy)-N-(4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-2-hydroxypropanamide:

To a stirred solution oftrans-N-(4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)oxirane-2-carboxamide(300 mg, 0.849 mmol, 1 equiv) and 4-chlorophenol (108 mg, 0.849 mmol, 1equiv) in DMF (10 mL), was added K₂CO₃ (234 mg, 1.698 mmol, 2 equiv) andthe resultant reaction mixture was heated at 100° C. overnight. Progressof the reaction was monitored by TLC and LCMS. After completion ofreaction, the reaction mixture was diluted with water (50 mL) andextracted with EtOAc (50 mL×2). The combined organic layer was washedwith water (30 mL), brine solution (30 mL×2), dried over anhydroussodium sulfate and concentrated under reduced pressure to obtain a crudemixture which was purified by reversed-phase HPLC to obtaintrans-3-(4-chlorophenoxy)-N-(4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-2-hydroxypropanamide(Compound 8-50 mg) as white solid. LCMS 481[M+H]⁺; ¹HNMR (400 MHz,DMSO-d₆) δ 7.94 (d, J=8.77 Hz, 1H), 7.69 (d, J=8.77 Hz, 1H), 7.34 (d,J=9.21 Hz, 4H), 6.97 (d, J=9.21 Hz, 4H), 5.94 (d, J=5.70 Hz, 1H), 4.45(s, 2H), 4.19 (br. s., 1H), 4.01-4.12 (m, 2H), 3.58 (br. s., 2H), 1.74(br. s., 4H), 1.23 (br. s., 4H).

Example 5 Synthesis oftrans-3-(4-chloro-3-fluorophenoxy)-N-(4-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclohexyl)-2-hydroxypropanamide

Step 1 Synthesis oftrans-N-(4-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclohexyl)oxirane-2-carboxamide:

To a stirred mixture oftrans-N-(4-aminocyclohexyl)-2-(4-chloro-3-fluorophenoxy)acetamide (1000mg, 3.18 mmol, 1 equiv) in DMF (30 mL), was added triethylamine (1.8 mL,12.72 mmol, 3 equiv), HOBT (643 mg, 4.77 mmol, 1.5 equiv) and EDC.HCl(643 mg, 4.77 mmol, 1.5 equiv). The reaction mixture was stirred at RTfor 30 min. Oxirane-2-carboxylic acid (420 mg, 4.77 mmol, 1.5 equiv) wasadded and the resultant reaction mixture was stirred at RT overnight.Reaction was monitored by LCMS. After completion of the reaction, thereaction mixture was diluted with water (100 mL) and extracted withEtOAc (2×100 mL) and washed with water and brine solution (2×50 mL),dried over anhydrous sodium sulfate and concentrated under reducedpressure to obtaintrans-N-(4-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclohexyl)oxirane-2-carboxamide(220 mg, 20% Yield) as a white solid. LCMS: 370 [M+1-1]⁺.

Step 2 Synthesis oftrans-3-(4-chloro-3-fluorophenoxy)-N-(4-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclohexyl)-2-hydroxypropanamide:

To a stirred solution oftrans-N-(4-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclohexyl)oxirane-2-carboxamide(100 mg, 0.27 mmol, 1 equiv) in DMF (10 mL) was added K₂CO₃ (75 mg, 0.54mmol, 2 equiv) followed by the addition of 4-chloro-3-fluorophenol (40mg, 0.27 mmol, 1 equiv). The resultant reaction mixture was heated at100° C. overnight. The reaction was monitored by TLC and LCMS. Aftercompletion of reaction, the reaction mixture was diluted with water (50mL) and extracted with EtOAc (2×50 mL) and washed with water and brinesolution (2×30 mL) and dried over anhydrous sodium sulfate andconcentrated under reduced pressure to obtain a crude mixture which waspurified by reversed-phase HPLC to obtaintrans-3-(4-chloro-3-fluorophenoxy)-N-(4-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclohexyl)-2-hydroxypropanamide(Compound 9-60 mg, 48% Yield) as a white solid. LCMS: 517 [M+H]⁺; ¹HNMR(400 MHz, DMSO-d₆) δ 7.97 (d, J=7.89 Hz, 1H), 7.70 (d, J=8.33 Hz, 1H),7.41-7.57 (m, 2H), 7.00-7.13 (m, 2H), 6.84 (d, J=8.33 Hz, 2H), 5.98 (br.s, 1H), 4.49 (s, 2H), 4.04-4.25 (m, 2H), 3.58 (br. s, 2H), 1.74 (s, 4H),1.23-1.45 (m, 4H).

Example 6 Synthesis oftrans-2-(4-chloro-3-fluorophenoxy)-N-(4-((3-(4-chlorophenoxy)-2-hydroxypropyl)amino)cyclohexyl)acetamide

To a stirred solution oftrans-N-(4-aminocyclohexyl)-2-(4-chloro-3-fluorophenoxy)acetamidetrifluoroacetate salt (200 mg, 0.63 mmol, 1 equiv) in DMF (10 mL) wasadded K₂CO₃ (264 mg, 1.9 mmol, 3 equiv) followed by the addition of2-((4-chlorophenoxy)methyl)oxirane (175 mg, 0.95 mmol, 1 equiv). Theresultant reaction mixture was heated at 100° C. overnight. The reactionwas monitored by TLC and LCMS. After completion of reaction, thereaction mixture was diluted with water (70 mL) and extracted with EtOAc(2×50 mL) and washed with water and brine solution (2×30 mL) and driedover anhydrous sodium sulfate and concentrated under reduced pressure toobtain a crude mixture which was purified by reversed-phase HPLC toobtaintrans-2-(4-chloro-3-fluorophenoxy)-N-(4-((3-(4-chlorophenoxy)-2-hydroxypropyl)amino)cyclohexyl)acetamide(Compound 10-20 mg, 15% Yield) as a white solid. LCMS: 485 [M+H]⁺; ¹HNMR(400 MHz, DMSO-d₆) δ 7.92 (d, J=8.33 Hz, 2H), 7.49 (t, J=8.55 Hz, 1H),7.31 (d, J=8.77 Hz, 2H), 7.06 (d, J=8.77 Hz, 1H), 6.96 (d, J=8.33 Hz,2H), 6.84 (d, J=8.77 Hz, 1H), 4.48 (s, 2H), 3.94 (d, J=5.26 Hz, 1H),3.85 (s, 2H), 3.56 (br. s., 2H), 1.90 (s, 4H), 1.75 (s, 4H).

Example 7 Synthesis of2-(4-chloro-3-fluorophenoxy)-N-((3S)-1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-3-yl)acetamide

Step 1 Synthesis of tert-butyl((3S)-1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-3-yl)carbamate:

To a stirred solution of tert-butyl (S)-piperidin-3-ylcarbamate (0.500g, 2.47 mmol, 1.0 equiv) in DMF (5 mL) was added2-((4-chloro-3-fluorophenoxy)methyl)oxirane (0.602 g, 2.98 mmol, 2.0equiv) at RT. The resulting reaction mixture was heated at 100° C. for12 hr. Product formation was confirmed by ¹H NMR spectroscopy. Thereaction was stopped by adding water and the resulting precipitate wasfiltered off. The obtained solid was washed with water (25 mL×2) anddried under vacuum to obtain tert-butyl((3S)-1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-3-yl)carbamate.(1.0 g 95% Yield, as a white solid). LMCS 403 [M+H]⁺.

Step 2 Synthesis of1-(((3S)-1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-3-yl)-λ⁴-azanyl)-2,2,2-trifluoroethan-1-onetrifluoroacetate salt:

To a stirred solution of tert-butyl((3S)-1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-3-yl)carbamate(1.0 g, 2.48 mmol, 1.0 equiv) in DCM (30 mL) was added trifluoroaceticacid (5 mL) at RT. The reaction mixture was allowed to stir at RTovernight. DCM and excess trifluoroacetic acid was removed under reducedpressure to obtain1-(((3S)-1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-3-yl)-λ⁴-azanyl)-2,2,2-trifluoroethan-1-onetrifluoroacetate salt (1.3 g, 100% Yield as an yellow oil). LCMS 303[M+H]⁺.

Step 3 Synthesis of2-(4-chloro-3-fluorophenoxy)-N-((3S)-1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-3-yl)acetamide:

To a solution of1-(43S)-1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-3-yl)Δ⁴-azanyl)-2,2,2-trifluoroethan-1-onetrifluoroacetate salt (1.0 g, 2.48 mmol, 1.0 equiv) in DMF (15 mL) wasadded 2-(4-chloro-3-fluorophenoxy)acetic acid (0.607 g, 2.97 mmol, 1.2equiv) and HATU (1.89 g, 4.96 mmol) at RT. The resulting reactionmixture was stirred for 10 minutes, and DIPEA (2.1 mL, 12.4 mmol) wasadded. The reaction mixture was allowed to stir at RT overnight. Productformation was confirmed by LCMS. The reaction mixture was diluted withwater (50 mL) and extracted with EtOAc (100 mL×2). The combined organicextracts were washed with water (50 mL×4), dried over anhydrous sodiumsulfate and concentrated. The crude product obtained was purified byreverse phase HPLC to obtain2-(4-chloro-3-fluorophenoxy)-N-((3S)-1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-3-yl)acetamide(Compound 11-30 mg, as an off-white solid). LCMS 489 [M+H]⁺; ¹HNMR (400MHz, DMSO-d₆) δ 7.90 (d, J=7.02 Hz, 1H), 7.30-7.54 (m, 2H), 7.03 (m,2H), 6.69-6.92 (m, 2H), 4.93 (br. s., 1H), 4.51 (s, 1H), 4.00 (d, J=7.02Hz, 1H), 3.84-3.94 (m, 2H), 3.81 (br. s., 1H), 2.69 (d, J=12.72 Hz, 1H),2.27-2.42 (m, 2H), 2.16 (m., 2H), 1.75 (br. s., 1H), 1.62 (d, J=9.21 Hz,2H), 1.46 (d, J=7.02 Hz, 1H), 1.32 (br. s., 1H), 1.23 (br. s., 1H).

Example 8 Synthesis of2-(4-chloro-3-fluorophenoxy)-N-((3R)-1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-3-yl)acetamide

Step 1 Synthesis of tert-butyl((3R)-1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-3-yl)carbamate:

To a stirred solution of tert-butyl (R)-piperidin-3-ylcarbamate (0.500g, 2.47 mmol, 1.0 equiv) in DMF (5 mL) was added2-((4-chloro-3-fluorophenoxy)methyl)oxirane (0.602 g, 2.98 mmol, 2.0equiv) at RT. The resulting reaction mixture was heated at 100° C. for12 h. Product formation was confirmed by ¹H NMR spectroscopy. Reactionwas stopped by adding water and the resulting precipitate was filteredoff. Obtained solid was washed with water (25 mL×2) and dried undervacuum to obtain tert-butyl((3R)-1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-3-yl)carbamate.(1.1 g as an white solid). LCMS: 403 [M+H]⁺.

Step 2 Synthesis of1-(((3R)-1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-3-yl)-λ⁴-azanyl)-2,2,2-trifluoroethan-1-onetrifluoroacetate salt:

To a stirred solution of tert-butyl((3R)-1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-3-yl)carbamate(1.0 g, 2.48 mmol, 1.0 equiv) in DCM (30 mL) was added trifluoroaceticacid (5 mL) at RT. the reaction mixture was allowed to stir at RTovernight. DCM and excess trifluoroacetic acid was removed under reducedpressure to obtain1-(((3R)-1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-3-yl)-λ⁴-azanyl)-2,2,2-trifluoroethan-1-onetrifluoroacetate salt (1.4 g, as an oil). LCMS: 303 [M+1-1]⁺.

Step 3 Synthesis of2-(4-chloro-3-fluorophenoxy)-N-((3R)-1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-3-yl)acetamide:

To a solution of1-(((3R)-1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-3-yl)-λ⁴-azanyl)-2,2,2-trifluoroethan-1-onetrifluoroacetate salt (1.0 g, 2.48 mmol, 1.0 equiv) in DMF (15 mL) wasadded 2-(4-chloro-3-fluorophenoxy)acetic acid (0.607 g, 2.97 mmol, 1.2equiv) and HATU (1.89 g, 4.96 mmol) at RT. The resulting reactionmixture was stirred for 10 minutes and then DIPEA (2.1 mL, 12.4 mmol)was added. The reaction mixture was allowed to stir at RT overnight.Product formation was confirmed by LCMS. The reaction mixture wasdiluted with water (50 mL) and extracted with EtOAc (100 mL×2). Thecombined organic extracts were washed with water (50 mL×4), dried overanhydrous sodium sulfate and concentrated. The crude product obtainedwas purified by reverse phase HPLC to obtain2-(4-chloro-3-fluorophenoxy)-N-((3R)-1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-3-yl)acetamide(Compound 12-10 mg, as an off-white solid). LCMS: 489 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 7.90 (d, J=7.02 Hz, 1H), 7.30-7.54 (m, 2H), 7.03(m, 2H), 6.69-6.92 (m, 2H), 4.93 (br. s., 1H), 4.51 (s, 1H), 4.00 (d,J=7.02 Hz, 1H), 3.84-3.94 (m, 2H), 3.81 (br. s., 1H), 2.69 (d, J=12.72Hz, 1H), 2.27-2.42 (m, 2H), 2.16 (m., 2H), 1.75 (br. s., 1H), 1.62 (d,J=9.21 Hz, 2H), 1.46 (d, J=7.02 Hz, 1H), 1.32 (br. s., 1H), 1.23 (br.s., 1H).

Example 9 Synthesis of2-(4-chloro-3-fluorophenoxy)-N-(1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-4-yl)acetamide

Step 1 Synthesis of tert-butyl(1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-4-yl)carbamate:

To a stirred solution of tert-butyl piperidin-4-ylcarbamate (0.500 g,2.500 mmol, 1.0 equiv) in DMF (5 mL) was added2-((4-chloro-3-fluorophenoxy)methyl)oxirane (0.507 g, 2.500 mmol, 1.0equiv) at RT. The resulting reaction mixture was heated at 100° C. for12 hr. Progress of the reaction was monitored by ¹H NMR. The reactionwas stopped by adding water and the resulting precipitate was filteredoff. The obtained solid was washed with water (25 mL×2) and dried undervacuum to obtain tert-butyl(1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-4-yl)carbamate(1.000 g, 99% Yield) as a white solid. LCMS: 403.3 [M+H]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 7.45 (t, J=8.77 Hz, 1H), 7.05 (dd, J=2.63, 11.40 Hz,1H), 6.84 (dd, J=1.75, 8.77 Hz, 1H), 6.74 (d, J=7.45 Hz, 1H), 4.86 (d,J=3.95 Hz, 1H), 3.98 (d, J=6.58 Hz, 1H), 3.82-3.93 (m, 2H), 3.17 (br.s., 1H), 2.74-2.90 (m, 2H), 2.26-2.42 (m, 2H), 1.90-2.09 (m, 2H),1.60-1.70 (m, 2H), 1.37 (s, 9H).

Step 2 Synthesis of1-(4-aminopiperidin-1-yl)-3-(4-chloro-3-fluorophenoxy)propan-2-oltrifluoroacetate salt:

To a stirred solution of tert-butyl(1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-4-yl)carbamate(1.00 g, 2.48 mmol, 1.0 equiv) in DCM (30 mL) was added trifluoroaceticacid (5 mL) at RT. The reaction mixture was allowed to stir at RTovernight. DCM and excess trifluoroacetic acid was removed under reducedpressure to obtain1-(4-aminopiperidin-1-yl)-3-(4-chloro-3-fluorophenoxy)propan-2-oltrifluoroacetate salt (1.00 g, 96% Yield) as an yellow oil. ¹HNMR (400MHz, DMSO-d₆) δ 9.60 (br. s., 1H), 8.15 (br. s., 2H), 7.50 (t, J=9.21Hz, 1H), 7.09 (d, J=11.40 Hz, 1H), 6.85 (d, J=7.89 Hz, 1H), 5.75 (br.s., 1H), 4.29 (br. s., 1H), 4.00 (br. s., 2H), 3.62 (d, J=10.96 Hz, 2H),3.28 (br. s., 2H), 3.18 (d, J=10.52 Hz, 3H), 2.07 (d, J=11.84 Hz, 2H),1.83-2.01 (m, 2H).

Step 3 Synthesis of2-(4-chloro-3-fluorophenoxy)-N-(1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-4-yl)acetamide:

To a solution of1-(4-aminopiperidin-1-yl)-3-(4-chloro-3-fluorophenoxy)propan-2-oltrifluoroacetate salt (1.00 g, 2.40 mmol, 1.0 equiv) in DMF (10 mL) wasadded 2-(4-chloro-3-fluorophenoxy)acetic acid (0.540 g, 2.64 mmol, 1.1equiv) and HATU (1.830 g, 4.80 mmol, 2.0 equiv) at RT. The reactionmixture was stirred for 10 minutes and then DIPEA (1.7 mL, 9.41 mmol,5.0 equiv) was added. The resultant reaction mixture was allowed to stirat RT overnight. Progress of the reaction was monitored by LCMS. Thereaction mixture was diluted with water (50 mL) and extracted with EtOAc(100 mL×2). The combined organic layer was washed with water (50 mL×4),dried over anhydrous sodium sulfate and concentrated under reducedpressure to obtain a crude compound which was purified by reverse phaseHPLC to obtain2-(4-chloro-3-fluorophenoxy)-N-(1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-4-yl)acetamide(Compound 13-0.500 g, 43% Yield) as an off-white solid. LCMS: 489.2[M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 7.97 (d, J=7.89 Hz, 1H), 7.45 (t,J=8.77 Hz, 1H), 7.49 (t, J=8.99 Hz, 1H), 7.05 (d, J=2.63 Hz, 1H), 7.07(d, J=2.63 Hz, 1H), 6.84 (d, J=8.77 Hz, 2H), 4.87 (br. s., 1H), 4.50 (s,2H), 4.00 (d, J=6.58 Hz, 1H), 3.83-3.95 (m, 2H), 3.60 (d, J=7.45 Hz,1H), 2.74-2.98 (m, 2H), 2.27-2.46 (m, 2H), 1.99-2.15 (m, 2H), 1.65 (br.s., 2H), 1.38-1.57 (m, 2H).

Example 10 Synthesis of2-(4-chloro-3-fluorophenoxy)-1-(4-((3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)amino)piperidin-1-yl)ethan-1-one

Step 1—Synthesis of tert-butyl(1-(2-(4-chloro-3-fluorophenoxy)acetyl)piperidin-4-yl)carbamate:

To a solution of tert-butyl piperidin-4-ylcarbamate (0.250 g, 1.25 mmol,1.0 equiv) in DMF (10 mL) was added 2-(4-chloro-3-fluorophenoxy)aceticacid (0.281 g, 1.37 mmol, 1.1 equiv) and HATU (0.950 g, 2.50 mmol, 2.0equiv) at RT. The reaction mixture was stirred for 10 minutes and thenDIPEA (0.7 mL, 3.75 mmol, 5.0 equiv) was added. The resultant reactionmixture was allowed to stir at RT overnight. Progress of the reactionwas monitored by LCMS. The reaction mixture was diluted with water (50mL) and extracted with ethyl acetate (50 mL×2). Combined organic layerwas washed with water (25 mL×4), dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to obtain the crude compound whichwas crystallized in hexane to obtain tert-butyl(1-(2-(4-chloro-3-fluorophenoxy)acetyl)piperidin-4-yl)carbamate (0.480g, 100% Yield) as an off-white solid. LCMS: 387.3 [M+H]⁺; ¹HNMR (400MHz, DMSO-d₆) δ7.46 (t, J=8.99 Hz, 1H), 7.05 (dd, J=2.85, 11.62 Hz, 1H),6.91 (d, J=7.02 Hz, 1H), 6.80 (dd, J=2.41, 8.99 Hz, 1H), 4.87 (q,J=14.62 Hz, 2H), 4.15 (d, J=13.59 Hz, 1H), 3.72 (d, J=14.03 Hz, 1H),3.48 (br. s., 1H), 3.07 (t, J=11.62 Hz, 1H), 2.68-2.78 (m, 1H), 1.74(br. s., 2H), 1.38 (s, 9H), 1.16-1.26 (m, 2H).

Step 2 Synthesis of1-(4-aminopiperidin-1-yl)-2-(4-chloro-3-fluorophenoxy)ethan-1-onetrifluoroacetate salt:

To a stirred solution of tert-butyl(1-(2-(4-chloro-3-fluorophenoxy)acetyl)piperidin-4-yl)carbamate (0.480g, 1.24 mmol, 1.0 equiv) in DCM (30 mL) was added trifluoroacetic acid(3 mL) at RT. the reaction mixture was allowed to stir at RT overnight.DCM and excess trifluoroacetic acid was removed under reduced pressureto obtain1-(4-aminopiperidin-1-yl)-2-(4-chloro-3-fluorophenoxy)ethan-1-onetrifluoroacetate salt (1.00 g, 100% Yield) as an yellow oil. ¹HNMR (400MHz, DMSO-d₆) δ 7.93 (br. s., 3H), 7.47 (t, J=8.77 Hz, 1H), 7.05 (dd,J=2.85, 11.62 Hz, 1H), 6.81 (dd, J=1.97, 8.99 Hz, 1H), 4.96 (d, J=14.47Hz, 1H), 4.87 (d, J=14.91 Hz, 1H), 4.32 (d, J=13.59 Hz, 1H), 3.82 (d,J=14.03 Hz, 1H), 3.27 (br. s., 1H), 3.08 (t, J=12.72 Hz, 1H), 2.63-2.79(m, 2H), 1.91 (br. s., 2H), 1.39-1.57 (m, 1H), 1.25-1.38 (m, 2H).

Step 3 Synthesis of2-(4-chloro-3-fluorophenoxy)-1-(4-((3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)amino)piperidin-1-yl)ethan-1-one:

To a stirred solution of1-(4-aminopiperidin-1-yl)-2-(4-chloro-3-fluorophenoxy)ethan-1-onetrifluoroacetate salt (0.500 g, 1.25 mmol, 1.0 equiv) in DMF (10 mL) wasadded K₂CO₃ (0.518, 3.75 mmol, 3.0 equiv) followed by the addition of2-((4-chloro-3-fluorophenoxy)methyl)oxirane (0.355 g, 1.75 mmol, 2.0equiv) at RT. The resulting reaction mixture was heated at 100° C. for12 hr. Product formation was confirmed by LCMS. The reaction was stoppedby adding water (70 mL) and extracted with EtOAc (2×50 mL). The combinedorganic layer was washed with water (5×30 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure to obtain a crudemixture which was purified by reverse phase HPLC to obtain2-(4-chloro-3-fluorophenoxy)-1-(4-((3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)amino)piperidin-1-yl)ethan-1-one(Compound 14-120 mg, 20% Yield) as an off-white solid. LCMS: 489.3[M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 7.48 (q, J=9.21 Hz, 2H), 6.98-7.11(m, 2H), 6.81 (d, J=8.77 Hz, 1H), 6.85 (d, J=8.77 Hz, 1H), 5.61 (br. s.,1H), 4.81-5.01 (m, 3H), 4.29 (d, J=13.16 Hz, 1H), 3.95-4.08 (m, 3H),3.82 (d, J=13.15 Hz, 1H), 2.97-3.16 (m, 3H), 2.81-2.97 (m, 2H),2.63-2.78 (m, 2H), 1.97 (br. s., 2H), 1.45 (br. s., 2H), 1.26 (d,J=19.29 Hz, 2H).

Example 11 Synthesis oftrans-5-chloro-N-(4-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclohexyl)benzofuran-2-carboxamide

Step 1 Synthesis of trans-tert-butyl(4-(5-chlorobenzofuran-2-carboxamido)cyclohexyl)carbamate:

To a solution of 5-chlorobenzofuran-2-carboxylic acid (0.274 g, 1.4mmol, 1.5 equiv) in DMF (10 mL) was added DIPEA (0.5 mL, 2.7 mmol, 3.0equiv) followed by the addition of HATU (0.706 g, 1.8 mmol, 2.0 equiv)and the resultant reaction mixture was stirred for 30 min.Trans-tert-butyl (4-aminocyclohexyl)carbamate (0.200 g, 0.90 mmol, 1.0equiv) was added and the reaction mixture was allowed to stir overnightat RT and the resulting precipitate was filtered off and washed withexcess methanol to obtain trans-tert-butyl(4-(5-chlorobenzofuran-2-carboxamido)cyclohexyl)carbamate (350 mg, 64%Yield) as an off-white solid. LCMS: 393 [M+H]⁺.

Step 2 Synthesis oftrans-N-(4-aminocyclohexyl)-5-chlorobenzofuran-2-carboxamidetrifluoroacetate salt:

To a stirred solution of trans-tert-butyl(4-(5-chlorobenzofuran-2-carboxamido)cyclohexyl)carbamate (350 mg, 0.89mmol, 1 equiv) in DCM (10 mL), was added trifluoroacetic acid (5 mL) andthe resultant reaction mixture was stirred at RT for 1 h under nitrogenatmosphere. Reaction was monitored by LCMS. After completion ofreaction, the reaction mixture was concentrated under reduced pressureto obtain sticky crude compound which was triturated with hexane (10 mL)and diethyl ether and dried under vacuum to obtaintrans-N-(4-aminocyclohexyl)-5-chlorobenzofuran-2-carboxamidetrifluoroacetate salt (500 mg, quantitative yield) as an off-whitesolid. LCMS: 293 [M+H]⁺.

Step 3—Synthesis oftrans-5-chloro-N-(4-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclohexyl)benzofuran-2-carboxamide:

To a solution oftrans-N-(4-aminocyclohexyl)-5-chlorobenzofuran-2-carboxamidetrifluoroacetate salt (0.200 g, 0.51 mmol, 1.0 equiv) in DCM (10 mL) wasadded DIPEA (0.3 mL, 1.5 mmol, 3.0 equiv) followed by the addition ofHATU (0.388 g, 1.02 mmol, 2.0 equiv). The resulting mixture was stirredfor 30 min. 2-(4-chloro-3-fluorophenoxy)acetic acid (0.164 g, 0.76 mmol,1.5 equiv) was added and the reaction mixture was allowed to stirovernight at RT and the resulting precipitate was filtered off andwashed with excess methanol to obtaintrans-5-chloro-N-(4-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclohexyl)benzofuran-2-carboxamide(Compound 17-100 mg, 42% Yield) as an off-white solid. LCMS: 479 [M+H]⁺;¹HNMR (400 MHz, DMSO-d₆) δ 8.61 (d, J=7.89 Hz, 1H), 8.01 (d, J=8.33 Hz,1H), 7.87 (d, J=2.19 Hz, 1H), 7.69 (d, J=8.77 Hz, 1H), 7.32-7.60 (m,3H), 7.07 (dd, J=2.63, 11.40 Hz, 1H), 6.85 (d, J=10.96 Hz, 1H), 4.51 (s,2H), 3.76 (d, J=9.21 Hz, 1H), 3.60 (br. s., 1H), 1.73-1.98 (m, 4H),1.28-1.54 (m, 4H).

Example 12 Synthesis oftrans-6-chloro-N-(4-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclohexyl)benzo[d]thiazole-2-carboxamide

Step 1—Synthesis of trans-tert-butyl(4-(6-chlorobenzo[d]thiazole-2-carboxamido)cyclohexyl)carbamate:

To a solution of 6-chlorobenzo[d]thiazole-2-carboxylic acid (0.025 g,0.11 mmol, 1.0 equiv) in DMF (10 mL) was added DIPEA (0.2 mL, 0.33 mmol,3.0 equiv) followed by the addition of HATU (0.089 g, 0.23 mmol, 2.0equiv) and the resulting mixture was stirred for 30 min.Trans-tert-butyl (4-aminocyclohexyl)carbamate (0.025 g, 0.11 mmol, 1.0equiv) was added and the reaction mixture was allowed to stir overnightat RT and the resulting precipitate was filtered off and washed withexcess methanol to obtain trans-tert-butyl(4-(6-chlorobenzo[d]thiazole-2-carboxamido)cyclohexyl)carbamate (60 mg,quantitative yield) as an off-white solid. LCMS: 410 [M+H]⁺; ¹HNMR (400MHz, DMSO-d₆) δ 9.04 (d, J=8.3 Hz, 1H), 8.39 (s, 1H), 8.11 (d, J=8.8 Hz,1H), 7.66 (d, J=9.2 Hz, 1H), 6.75 (d, J=7.0 Hz, 1H), 3.71 (br. s., 2H),3.18 (br. s., 2H), 1.80 (d, J=12.7 Hz, 3H), 1.54 (d, J=9.6 Hz, 2H), 1.38(s, 9H), 1.25 (d, J=11.4 Hz, 2H).

Step 2—Synthesis oftrans-N-(4-aminocyclohexyl)-6-chlorobenzo[c]thiazole-2-carboxamidetrifluoroacetate salt:

To a stirred solution of trans-tert-butyl(4-(6-chlorobenzo[d]thiazole-2-carboxamido)cyclohexyl)carbamate (60 mg,0.16 mmol, 1 equiv) in DCM (2 mL), was added trifluoroacetic acid (3 mL)and the resultant reaction mixture was stirred at RT for 1 h undernitrogen atmosphere. Reaction was monitored by LCMS. After completion ofreaction, the reaction mixture was concentrated under reduced pressureto obtain sticky crude compound which was triturated with hexane (10mL), diethyl ether (10 mL) and dried under vacuum to obtaintrans-N-(4-aminocyclohexyl)-6-chlorobenzo[d]thiazole-2-carboxamidetrifluoroacetate salt (70 mg, quantitative yield) as an off-white solid.LCMS: 310 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 9.12 (d, J=8.3 Hz, 1H),8.40 (s, 1H), 8.12 (d, J=8.8 Hz, 1H), 7.76 (br. s., 2H), 7.67 (dd,J=2.2, 8.8 Hz, 1H), 3.75 (br. s., 2H), 2.98 (br. s., 2H), 1.97 (d,J=11.0 Hz, 2H), 1.89 (d, J=10.5 Hz, 2H), 1.68-1.47 (m, 2H), 1.47-1.34(m, 2H).

Step 3—Synthesis oftrans-6-chloro-N-(4-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclohexyl)benzo[c]thiazole-2-carboxamide:

To a solution oftrans-N-(4-aminocyclohexyl)-6-chlorobenzo[d]thiazole-2-carboxamidetrifluoroacetate salt (0.070 g, 0.15 mmol, 1.0 equiv) in DMF (10 mL) wasadded DIPEA (0.1 mL, 0.45 mmol, 3.0 equiv) followed by the addition ofHATU (0.114 g, 0.30 mmol, 2.0 equiv) and the resulting mixture wasstirred for 30 min. 2-(4-chloro-3-fluorophenoxy)acetic acid (0.40 g,0.18 mmol, 1.5 equiv) was added and the reaction mixture was allowed tostir overnight at RT and the resulting precipitate was filtered off andwashed with excess methanol to obtaintrans-6-chloro-N-(4-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclohexyl)benzo[d]thiazole-2-carboxamide(Compound 18-15 mg, 18% Yield) as a white solid. LCMS: 497 [M+H]⁺; ¹HNMR(400 MHz, DMSO-d₆) δ 9.05 (d, J=9.21 Hz, 1H), 8.39 (br. s., 1H), 8.12(d, J=8.33 Hz, 1H), 7.99 (d, J=8.33 Hz, 1H), 7.66 (d, J=8.77 Hz, 1H),7.50 (t, J=8.77 Hz, 1H), 7.07 (d, J=13.59 Hz, 1H), 6.86 (d, J=11.40 Hz,1H), 4.51 (s, 2H), 3.77 (br. s., 1H), 3.60 (br. s., 1H), 1.81 (d,J=13.59 Hz, 4H), 1.59 (d, J=11.40 Hz, 2H), 1.39 (d, J=11.84 Hz, 2H).

Example 13 Synthesis oftrans-5-chloro-N-(4-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclohexyl)-2,3-dihydrobenzofuran-2-carboxamide

Step 1—Synthesis of trans-tert-butyl(4-(5-chloro-2,3-dihydrobenzofuran-2-carboxamido)cyclohexyl)carbamate:

To a solution of 5-chloro-2,3-dihydrobenzofuran-2-carboxylic acid (0.050g, 0.25 mmol, 1.0 equiv) in DMF (05 mL) was added DIPEA (0.2 mL, 0.75mmol, 3.0 equiv) followed by the addition of HATU (0.190 g, 0.50 mmol,2.0 equiv) and the resulting mixture was stirred for 30 min.Trans-tert-butyl (4-aminocyclohexyl)carbamate (0.200 g, 0.90 mmol, 1.0equiv) was added and the reaction mixture was allowed to stir overnightat RT and the resulting precipitate was filtered off and washed withexcess methanol to obtain trans-tert-butyl(4-(5-chloro-2,3-dihydrobenzofuran-2-carboxamido)cyclohexyl)carbamate(100 mg, quantitative yield) as an off-white solid. LCMS: 394 [M+1-1]⁺.

Step 2 Synthesis oftrans-N-(4-aminocyclohexyl)-5-chloro-2,3-dihydrobenzofuran-2-carboxamidetrifluoroacetate salt:

To a stirred solution of trans-tert-butyl(4-(5-chloro-2,3-dihydrobenzofuran-2-carboxamido)cyclohexyl)carbamate(100 mg, 0.25 mmol, 1 equiv) in DCM (10 mL), was added trifluoroaceticacid (5 mL) and the resultant reaction mixture was stirred at RT for 1 hunder nitrogen atmosphere. Reaction was monitored by LCMS. Aftercompletion of reaction, the reaction mixture was concentrated underreduced pressure to obtain sticky crude compound which was trituratedwith hexane (10 mL) and diethyl ether and dried under vacuum to obtaintrans-N-(4-aminocyclohexyl)-5-chloro-2,3-dihydrobenzofuran-2-carboxamidetrifluoroacetate salt (100 mg, quantitative yield) as an off-whitesolid. LCMS: 294 [M+H]⁺.

Step 3 Synthesis oftrans-5-chloro-N-(4-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclohexyl)-2,3-dihydrobenzofuran-2-carboxamide:

To a solution oftrans-N-(4-aminocyclohexyl)-5-chloro-2,3-dihydrobenzofuran-2-carboxamidetrifluoroacetate salt (0.100 g, 0.25 mmol, 1.0 equiv) in DMF (10 mL) wasadded DIPEA (0.13 mL, 0.75 mmol, 3.0 equiv) followed by the addition ofHATU (0.190 g, 0.50 mmol, 2.0 equiv). The resulting mixture was stirredfor 30 min. 2-(4-chloro-3-fluorophenoxy)acetic acid (0.083 g, 0.38 mmol,1.5 equiv) was added and the reaction mixture was allowed to stirovernight at RT and the resulting precipitate was filtered off andwashed with excess methanol to obtaintrans-5-chloro-N-(4-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclohexyl)-2,3-dihydrobenzofuran-2-carboxamide(Compound 19—70 mg, 60% Yield) as an off-white solid. LCMS: 481 [M+H]⁺;¹HNMR (400 MHz, DMSO-d₆) δ 8.03 (d, J=7.45 Hz, 1H), 7.96 (d, J=8.33 Hz,1H), 7.49 (t, J=8.99 Hz, 1H), 7.26 (br. s., 1H), 7.15 (d, J=8.77 Hz,1H), 7.04 (d, J=4.38 Hz, 1H), 6.84 (d, J=8.33 Hz, 2H), 5.06-5.17 (m,1H), 4.49 (s, 2H), 3.56 (br. s., 2H), 3.43 (d, J=10.09 Hz, 1H), 3.18(br. s., 1H), 1.77 (br. s., 4H), 1.32 (br. s., 4H).

Example 14 Synthesis of5-chloro-N-(1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-4-yl)-2,3-dihydrobenzofuran-2-carboxamide

To a solution of1-(4-aminopiperidin-1-yl)-3-(4-chloro-3-fluorophenoxy)propan-2-oltrifluoroacetate salt (0.105 g, 0.25 mmol, 1.0 equiv) in DMF (10 mL) wasadded 5-chloro-2,3-dihydrobenzofuran-2-carboxylic acid (0.050 g, 0.25mmol, 1.0 equiv) and HATU (0.190 g, 9.0 mmol, 2.0 equiv) at RT. Theresulting reaction mixture was stirred for 10 min and then DIPEA (0.2mL, 0.75 mmol, 3.0 equiv) was added. The reaction mixture was allowed tostir at RT overnight. Product formation was confirmed by LCMS. Thereaction mixture was diluted with water (50 mL) and extracted with ethylacetate (100 mL×2). Combined organic extracts were washed with water (50mL×4), dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to obtain crude which was purified by reversed phase HPLC toobtain5-chloro-N-(1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-4-yl)-2,3-dihydrobenzofuran-2-carboxamide(Compound 20-10 mg) as an off-white solid. LCMS: 483 [M+1-1]⁺; ¹HNMR(400 MHz, DMSO-d₆) δ 8.05 (d, J=8.3 Hz, 1H), 7.46 (t, J=8.8 Hz, 1H),7.26 (br. s., 1H), 7.15 (d, J=7.9 Hz, 1H), 7.06 (d, J=11.0 Hz, 1H), 6.83(d, J=8.3 Hz, 2H), 5.08-5.17 (m, 1H), 4.87 (br. s., 1H), 4.00 (d, J=6.6Hz, 1H), 3.89 (br. s., 1H), 3.57 (br. s., 1H), 3.45 (dd, J=16.2, 11.0Hz, 2H), 3.14-3.23 (m, 1H), 2.80 (br. s., 2H), 2.33 (br. s., 2H), 2.06(d, J=17.1 Hz, 2H), 1.65 (br. s., 2H), 1.48 ppm (d, J=12.3 Hz, 2H).

Example 15 Synthesis of6-chloro-N-(1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-4-yl)-2-naphthamide

To a solution of1-(4-aminopiperidin-1-yl)-3-(4-chloro-3-fluorophenoxy)propan-2-oltrifluoroacetate salt (0.202 g, 0.485 mmol, 1.0 equiv) in DMF (10 mL)was added 6-chloro-2-naphthoic acid (0.100 g, 0.485 mmol, 1.0 equiv) andHATU (0.369 g, 0.970 mmol, 2.0 equiv) at RT. The resulting reactionmixture was allowed to stir for 10 min. DIPEA (187 mg, 1.48 mmol, 3.0equiv) was added and the resultant reaction mixture was allowed to stirat RT overnight. Product formation was confirmed by LCMS. The reactionmixture was diluted with water (50 mL) and extracted with ethyl acetate(100 mL×2). Combined organic extracts were washed with water (50 mL×4),dried over anhydrous Na₂SO₄ and concentrated to obtain crude which waspurified by reversed phase HPLC to obtain6-chloro-N-(1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-4-yl)-2-naphthamide(Compound 21-60 mg, 26% Yield) as an off-white solid. LCMS: 491 [M+H]⁺;¹HNMR (400 MHz, DMSO-d₆) δ 8.40-8.53 (m, 2H), 8.05-8.18 (m, 2H), 7.98(s, 2H), 7.60 (dd, J=8.8, 1.8 Hz, 1H), 7.47 (t, J=8.8 Hz, 1H), 7.08 (dd,J=11.8, 2.6 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H), 4.91-5.07 (m, 1H),3.98-4.11 (m, 2H), 3.79-3.98 (m, 2H), 2.93-3.10 (m, 3H), 2.31 (d, J=13.6Hz, 3H), 1.85 (d, J=11.0 Hz, 2H), 1.66 (d, J=11.8 Hz, 2H).

Example 16 Synthesis of6-chloro-N-(1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-4-yl)quinoline-2-carboxamide

To a solution of1-(4-aminopiperidin-1-yl)-3-(4-chloro-3-fluorophenoxy)propan-2-ol (0.138g, 0.48 mmol, 1.0 equiv) in DMF (10 mL) was added6-chloroquinoline-2-carboxylic acid (0.100 g, 0.48 mmol, 1.0 equiv) andHATU (0.365 g, 0.96 mmol, 2.0 equiv) at RT. The resulting reactionmixture was stir for 10 min. DIPEA (0.24 mL, 1.44 mmol, 3.0 equiv) wasadded and the resultant reaction mixture was allowed to stir at RTovernight. Product formation was confirmed by LCMS. The reaction mixturewas diluted with water (50 mL) and extracted with ethyl acetate (100mL×2). Combined organic extracts were washed with water (50 mL×4), driedover anhydrous Na₂SO₄ and concentrated under reduced pressure to obtaincrude which was purified by reversed phase HPLC to obtain6-chloro-N-(1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-4-yl)quinoline-2-carboxamide(Compound 22-15 mg, 6.5% Yield) white solid. LCMS: 492 [M+H]⁺; ¹HNMR(400 MHz, DMSO-d₆) δ 8.68 (d, J=8.3 Hz, 1H), 8.53 (s, 1H), 8.24 (d,J=2.2 Hz, 1H), 8.17 (dd, J=4.8, 8.8 Hz, 2H), 7.88 (dd, J=2.4, 9.0 Hz,1H), 7.47 (t, J=9.0 Hz, 1H), 7.06 (d, J=3.1 Hz, 1H), 6.86 (d, J=8.8 Hz,1H), 4.90 (br. s., 1H), 4.04 (d, J=7.0 Hz, 1H), 3.95-3.86 (m, 2H), 3.85(br. s., 1H), 3.00-2.82 (m, 2H), 2.40-2.27 (m, 2H), 2.20-2.05 (m, 2H),1.79 (br. s., 2H), 1.71 (d, J=11.0 Hz, 2H).

Example 17 Synthesis oftrans-6-chloro-N-(4-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclohexyl)quinoline-2-carboxamide

To a solution oftrans-N-(4-aminocyclohexyl)-2-(4-chloro-3-fluorophenoxy)acetamide (0.200g, 0.6 mmol, 1.0 equiv) in DMF (10 mL) was added6-chloroquinoline-2-carboxylic acid (0.138 g, 0.6 mmol, 1.0 equiv) andHATU (0.456 g, 1.2 mmol, 2.0 equiv) at RT. The reaction mixture was stirfor 10 min. DIPEA (0.31 mL, 1.8 mmol, 3.0 equiv) was added and theresultant reaction mixture was allowed to stir at RT overnight. Productformation was confirmed by LCMS. The reaction mixture was diluted withwater (50 mL) and extracted with ethyl acetate (100 mL×2). Combinedorganic extracts were washed with water (50 mL×4), dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to obtain crude which waspurified by reversed phase HPLC to obtaintrans-6-chloro-N-(4-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclohexyl)quinoline-2-carboxamide(Compound 23-110 mg, 34% Yield) as an off-white solid. LCMS: 490 [M+H]⁺;¹HNMR (400 MHz, DMSO-d₆) δ 8.66 (d, J=8.3 Hz, 1H), 8.54 (d, J=8.3 Hz,1H), 8.33-8.14 (m, 3H), 8.01 (d, J=7.9 Hz, 1H), 7.88 (d, J=9.2 Hz, 1H),7.50 (t, J=8.8 Hz, 1H), 7.11-7.01 (m, 1H), 6.86 (d, J=8.3 Hz, 1H), 4.52(s, 2H), 3.83 (d, J=7.5 Hz, 1H), 3.65 (br. s., 1H), 2.01-1.71 (m, 4H),1.69-1.53 (m, 2H), 1.47-1.32 (m, 2H).

Example 18 Synthesis oftrans-N-(4-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclohexyl)furo[2,3-c]pyridine-2-carboxamide

To a solution oftrans-N-(4-aminocyclohexyl)-2-(4-chloro-3-fluorophenoxy)acetamide (0.200g, 0.6 mmol, 1.0 equiv) in DMF (10 mL) was addedfuro[2,3-c]pyridine-2-carboxylic acid (0.108 g, 0.6 mmol, 1.0 equiv) andHATU (0.456 g, 1.2 mmol, 2.0 equiv) at RT. The reaction mixture was stirfor 10 min. DIPEA (0.31 mL, 1.8 mmol, 3.0 equiv) was added and theresultant reaction mixture continued stirring at RT for overnight.Product formation was confirmed by LCMS. The reaction mixture wasdiluted with water (50 mL) and extracted with ethyl acetate (100 mL×2).Combined organic extracts were washed with water (50 mL×4), dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to obtain crudewhich was purified by reversed phase HPLC to obtaintrans-N-(4-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclohexyl)furo[2,3-c]pyridine-2-carboxamide(Compound 24-90 mg, 30% Yield) as an off white solid. LCMS: 446 [M+H]⁺;¹HNMR (400 MHz, DMSO-d₆) δ 9.04 (s, 1H), 8.79 (d, J=7.9 Hz, 1H), 8.47(d, J=5.3 Hz, 1H), 8.01 (d, J=8.3 Hz, 1H), 7.81 (d, J=5.3 Hz, 1H), 7.60(s, 1H), 7.50 (t, J=9.0 Hz, 1H), 7.13-7.00 (m, 1H), 6.86 (d, J=8.3 Hz,1H), 4.51 (s, 2H), 3.78 (br. s., 1H), 3.63 (br. s., 1H), 1.82 (d, J=16.2Hz, 4H), 1.57-1.30 (m, 4H).

Example 19 Synthesis of2-(4-chloro-3-fluorophenoxy)-N-(1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)-2,2,6,6-tetramethylpiperidin-4-yl)acetamide

Step 1—Synthesis of1-(4-amino-2,2,6,6-tetramethylpiperidin-1-yl)-3-(4-chloro-3-fluorophenoxy)propan-2-ol:

To a stirred solution of 2,2,6,6-tetramethylpiperidin-4-amine (1.00 g,6.39 mmol, 1.0 equiv) in DMF (10 mL) was added2-((4-chloro-3-fluorophenoxy)methyl)oxirane (1.19 g, 6.39 mmol, 1.0equiv) at RT. The resulting reaction mixture was heated at 100° C. for12 h. Progress of the reaction was monitored by ¹HNMR. Reaction wasquenched by adding water and extracted with ethyl acetate (100 mL×2).Combined organic layer was washed with water (50 mL×4), dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The resultingcrude material was triturated with hexane and diethyl ether to obtain1-(4-amino-2,2,6,6-tetramethylpiperidin-1-yl)-3-(4-chloro-3-fluorophenoxy)propan-2-ol(0.330 g, 15% Yield) as an off-white solid. LCMS: 359.3 [M+H]⁺; ¹HNMR(400 MHz, DMSO-d₆) δ 7.51-7.39 (m, 1H), 7.06 (dd, J=2.9, 11.6 Hz, 1H),6.83 (dd, J=1.8, 8.8 Hz, 1H), 4.97 (br. s., 1H), 4.05-3.95 (m, 1H), 3.89(dd, J=5.9, 9.9 Hz, 1H), 3.85-3.74 (m, 1H), 2.81-2.57 (m, 3H), 1.69 (d,J=11.4 Hz, 2H), 1.13-1.06 (m, 6H), 1.01-0.88 (m, 6H).

Step-2: Synthesis of2-(4-chloro-3-fluorophenoxy)-N-(1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)-2,2,6,6-tetramethylpiperidin-4-yl)acetamide:

To a solution of1-(4-amino-2,2,6,6-tetramethylpiperidin-1-yl)-3-(4-chloro-3-fluorophenoxy)propan-2-ol(0.169 g, 0.472 mmol, 1.0 equiv) in DMF (2 mL) was added2-(4-chloro-3-fluorophenoxy)acetic acid (0.096 g, 0.472 mmol, 1.0 equiv)and HATU (0.358 g, 0.944 mmol, 2.0 equiv) at RT. The reaction mixturewas stirred for 10 min and then DIPEA (0.4 mL, 2.36 mmol, 5.0 equiv) wasadded. The resultant reaction mixture was allowed to stir at RT forovernight. Progress of the reaction was monitored by LCMS. The reactionmixture was diluted with water (50 mL) and extracted with ethyl acetate(100 mL×2). Combined organic layer was washed with water (50 mL×4),dried over anhydrous Na₂SO₄ and concentrated under reduced pressure toobtain the crude compound which was purified by reversed phase HPLC toobtain2-(4-chloro-3-fluorophenoxy)-N-(1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)-2,2,6,6-tetramethylpiperidin-4-yl)acetamide(Compound 25—0.015 g, 6% Yield) as an off-white solid. LCMS: 545.3[M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 7.54-7.38 (m, 2H), 7.09 (d, J=9.6 Hz,1H), 6.98 (d, J=13.6 Hz, 1H), 6.88-6.73 (m, 2H), 5.76 (br. s., 1H), 5.08(d, J=15.3 Hz, 1H), 5.01-4.85 (m, 2H), 4.00 (br. s., 2H), 1.69 (br. s.,2H), 1.23 (br. s., 12H).

Example 20 Synthesis of2-(4-chloro-3-fluorophenoxy)-N-(1-(3-(4-chloro-3-fluorophenoxy)propyl)piperidin-4-yl)acetamide

Step 1 Synthesis of 4-(3-bromopropoxy)-2-chloro-1-fluorobenzene:

To solution of 3-chloro-4-fluorophenol (0.100 g, 0.68 mmol, 1.0 equiv)in ethanol (5 mL) was added K₂CO₃ (0.187 g, 1.36 mmol, 2.0 equiv)followed by the addition of 3-chloro-4-fluorophenol (0.151 g, 0.75 mmol,1.1 equiv). The resulting reaction mixture was heated at 80° C. forovernight. Product formation was confirmed by NMR spectroscopy. Aftercompletion of reaction the reaction mixture was diluted with water (20mL) and extracted with ethyl acetate (50 mL×2). Combined organic layerwas washed with water (20 mL), dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to obtain the crude compound whichwas purified by flash chromatography (0-30% ethyl acetate in hexane asan eluent) to obtain 4-(3-bromopropoxy)-2-chloro-1-fluorobenzene (0.090g, 50% Yield) as a yellow semi-solid. ¹HNMR (400 MHz, DMSO-d₆)δ7.57-7.33 (m, 1H), 7.14-7.03 (m, 1H), 6.90-6.76 (m, 1H), 4.22-3.96 (m,3H), 3.71-3.55 (m, 1H), 2.30-2.09 (m, 1H), 1.10 (t, J=7.0 Hz, 2H).

Step 2—Synthesis of tert-butyl(1-(3-(4-chloro-3-fluorophenoxy)propyl)piperidin-4-yl)carbamate:

To solution of tert-butyl piperidin-4-ylcarbamate (0.067 g, 0.36 mmol,1.0 equiv) in DMF (1 mL) was added K₂CO₃ (0.059 g, 0.430 mmol, 1.2equiv) followed by the addition of4-(3-bromopropoxy)-2-chloro-1-fluorobenzene (0.090 g, 0.36 mmol, 1.0equiv). The resulting reaction mixture was heated at 100° C. forovernight. Product formation was confirmed by NMR spectroscopy. Aftercompletion of reaction the reaction mixture was diluted with water (20mL) and extracted with ethyl acetate (50 mL×2). Combined organic layerwas washed with water (20 mL×4), dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to obtain tert-butyl(1-(3-(4-chloro-3-fluorophenoxy)propyl)piperidin-4-yl)carbamate (0.056g, 50% Yield) as a crude which was used for next step without anyfurther purification. LCMS: 387.3 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ7.55-7.36 (m, 1H), 7.11-7.03 (m, 1H), 6.83 (t, J=8.8 Hz, 1H), 6.71 (d,J=7.5 Hz, 1H), 4.14 (t, J=6.4 Hz, 1H), 4.08-3.93 (m, 1H), 3.17 (br. s.,2H), 2.76 (br. s., 1H), 2.27-2.05 (m, 2H), 1.89-1.77 (m, 2H), 1.64 (br.s., 3H), 1.57-1.44 (m, 1H), 1.37 (s, 9H).

Step 3—Synthesis of1-(3-(4-chloro-3-fluorophenoxy)propyl)piperidin-4-amine trifluoroacetatesalt:

To a stirred solution of tert-butyl(1-(3-(4-chloro-3-fluorophenoxy)propyl)piperidin-4-yl)carbamate (0.056g, 0.145 mmol, 1.0 equiv) in DCM (30 mL) was added trifluoroacetic acid(1 mL) at RT. The reaction mixture was allowed to stir at RT overnight.DCM and excess of trifluoroacetic acid was removed under reducedpressure to obtain1-(3-(4-chloro-3-fluorophenoxy)propyl)piperidin-4-amine trifluoroacetatesalt (0.100 g, quantitative yield) as an oil. LCMS: 287.3 [M+H]⁺; ¹HNMR(400 MHz, DMSO-d₆) δ 8.24 (br. s., 2H), 7.52-7.41 (m, 1H), 7.16-6.98 (m,1H), 6.84 (d, J=6.6 Hz, 1H), 4.21-3.95 (m, 1H), 3.55 (d, J=11.0 Hz, 1H),3.32 (br. s., 2H), 3.09 (br. s., 2H), 3.02 (br. s., 1H), 2.95 (br. s.,1H), 2.23-1.96 (m, 4H), 1.78 (d, J=11.0 Hz, 2H), 1.67 (d, J=11.8 Hz,1H).

Step 4—Synthesis of2-(4-chloro-3-fluorophenoxy)-N-(1-(3-(4-chloro-3-fluorophenoxy)propyl)piperidin-4-yl)acetamide:

To a solution of 1-(3-(4-chloro-3-fluorophenoxy)propyl)piperidin-4-aminetrifluoroacetate salt (0.627 g, 1.93 mmol, 1.0 equiv) in DMF (5 mL) wasadded 2-(4-chloro-3-fluorophenoxy)acetic acid (0.394 g, 1.93 mmol, 1.0equiv) and HATU (1.46 g, 3.86 mmol, 2.0 equiv) at RT. The reactionmixture was stirred for 10 minutes and then DIPEA (1 mL, 5.79 mmol, 5.0equiv) was added. The resultant reaction mixture was allowed to stir atRT for overnight. Progress of the reaction was monitored by LCMS. Thereaction mixture was diluted with water (50 mL) and extracted with ethylacetate (100 mL×2). Combined organic layer was washed with water (50mL×4), dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to obtain the crude compound which was purified by reversedphase HPLC to obtain2-(4-chloro-3-fluorophenoxy)-N-(1-(3-(4-chloro-3-fluorophenoxy)propyl)piperidin-4-yl)acetamide(Compound 28-0.020 g, 3% Yield) as an off-white solid. LCMS: 473.2[M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 7.98 (d, J=7.9 Hz, 1H), 7.57-7.41 (m,2H), 7.04 (s, 1H), 7.07 (s, 1H), 6.83 (t, J=9.6 Hz, 2H), 4.50 (s, 2H),4.01 (t, J=6.1 Hz, 2H), 3.60 (br. s., 1H), 2.80 (d, J=11.4 Hz, 2H), 2.38(t, J=6.8 Hz, 2H), 1.95 (t, J=10.7 Hz, 2H), 1.92-1.82 (m, 2H), 1.68 (d,J=9.6 Hz, 2H), 1.54-1.42 (m, 2H).

Example 21 Synthesis of5-chloro-N-(1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-4-yl)benzofuran-2-carboxamide

To a solution of1-(4-aminopiperidin-1-yl)-3-(4-chloro-3-fluorophenoxy)propan-2-oltrifluoroacetate salt (0.200 g, 0.48 mmol, 1.0 equiv) in DMF (10 mL) wasadded 5-chlorobenzofuran-2-carboxylic acid (0.095 g, 0.48 mmol, 1.0equiv) and HATU (0.364 g, 0.96 mmol, 2.0 equiv) at RT. The resultingreaction mixture was stir at RT for 10 min and DIPEA (0.3 mL, 1.44 mmol,3.0 equiv) was added. The reaction mixture was allowed to stir at RTovernight Product formation was confirmed by LCMS. After completion ofreaction the reaction mixture was diluted with water (50 mL) andextracted with ethyl acetate (100 mL×2). Combined organic extracts werewashed with water (50 mL×4), dried over anhydrous Na₂SO₄ andconcentrated. The crude product was purified by reverse phase HPLC toobtain5-chloro-N-(1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-4-yl)benzofuran-2-carboxamide(Compound 29-50 mg, 21% yield) as a white solid. LCMS: 481.2 [M+H]⁺;¹HNMR (500 MHz, DMSO-d₆) δ 8.65 (d, J=7.9 Hz, 1H), 7.87 (d, J=2.3 Hz,1H), 7.70 (d, J=8.8 Hz, 1H), 7.55-7.43 (m, 3H), 7.08 (dd, J=11.5, 2.9Hz, 1H), 6.89-6.82 (m, 1H), 4.92 (s, 1H), 4.02 (dd, J=9.6, 3.0 Hz, 1H),3.95-3.86 (m, 3H), 3.76 (s, 1H), 3.34 (s, 9H), 2.94 (d, J=11.6 Hz, 1H),2.88 (s, 1H), 2.10 (t, J=12.7 Hz, 2H), 1.74 (s, 2H), 1.63 (t, J=12.3 Hz,2H).

Example 22 Synthesis oftrans-6-chloro-N-(4-((3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)amino)cyclohexyl)quinoline-2-carboxamide

Step 1—Synthesis of trans-tert-butyl(4-(6-chloroquinoline-2-carboxamido)cyclohexyl)carbamate:

To a stirred mixture of 6-chloroquinoline-2-carboxylic acid (100 mg,0.48 mmol, 1 equiv) and trans-tert-butyl (4-aminocyclohexyl)carbamate(103 mg, 0.48 mmol, 1 equiv) in DMF (5 mL) was added HATU (365 mg, 0.96mmol, 2 equiv) and continued stir at RT for 30 min. DIPEA (0.3 ml, 1.44mmol, 3 equiv) was added and again stirred at RT for overnight. Reactionprogress was monitored by LCMS. After completion of reaction, thereaction mixture was poured into water (50 mL), the resulting yellowprecipitate was filtered off and again washed with water (20 mL×2). Thusobtained solid was dried under vacuum to obtain trans-tert-butyl(4-(6-chloroquinoline-2-carboxamido)cyclohexyl)carbamate (120 mg,71.85%) as a yellow solid. LCMS: 404.6 [M+H]⁺

Step 2—Synthesis oftrans-N-(4-aminocyclohexyl)-6-chloroquinoline-2-carboxamidetrifluoroacetate salt:

To a stirred solution of trans-tert-butyl(4-(6-chloroquinoline-2-carboxamido)cyclohexyl)carbamate (120 mg, 0.297mmol, 1 equiv) in DCM (5 mL), was added TFA (0.5 mL) and the resultantreaction mixture was stirred at RT for overnight under nitrogenatmosphere. Reaction was monitored by LCMS. After completion ofreaction, the reaction mixture was concentrated under reduced pressureto obtain trans-N-(4-aminocyclohexyl)-6-chloroquinoline-2-carboxamidetrifluoroacetate salt (130 mg, quant. yield) as a light pink solid.LCMS: 304.4 [M+H]⁺

Step 3—Synthesis oftrans-6-chloro-N-(4-((3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)amino)cyclohexyl)quinoline-2-carboxamide:

To a stirred mixture oftrans-N-(4-aminocyclohexyl)-6-chloroquinoline-2-carboxamidetrifluoroacetate salt (130 mg, 0.311 mmol, 1 equiv) and K₂CO₃ (130 mg,0.935 mmol, 3 equiv) in DMF (10 mL) was stirred at RT for 30 minute.2-((4-chloro-3-fluorophenoxy)methyl)oxirane (63 mg, 0.311 mmol, 1 equiv)was added and heated at 70° C. for overnight. Reaction was monitored byLCMS. After completion of reaction, the reaction mixture was poured intoice cold water (50 m1) and extracted with EtOAc (2×30 mL). Combinedorganic layer was washed with water (4×20 mL), brine solution (20 mL),dried over anhydrous sodium sulfate and concentrated under reducedpressure to obtain crude product which was purified by reversed-phaseHPLC to obtaintrans-6-chloro-N-(4-((3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)amino)cyclohexyl)quinoline-2-carboxamide(Compound 30—35 mg, 30%) as an off white solid. LCMS: 506.4 [M+H]⁺;¹HNMR (500 MHz, DMSO-d₆) δ 8.65 (d, J=8.5 Hz, 1H), 8.54 (d, J=8.6 Hz,1H), 8.32 (s, 1H), 8.25 (d, J=2.5 Hz, 1H), 8.17 (t, J=8.7 Hz, 2H), 7.88(dd, J=9.0, 2.5 Hz, 1H), 7.47 (t, J=8.8 Hz, 1H), 7.09 (dd, J=11.5, 2.9Hz, 1H), 6.85 (dd, J=8.9, 2.8 Hz, 1H), 4.00 (d, J=7.1 Hz, 1H), 3.92 (d,J=8.8 Hz, 2H), 3.81 (d, J=10.9 Hz, 1H), 2.79 (d, J=11.8 Hz, 1H), 2.69(d, J=8.6 Hz, 1H), 1.98 (d, J=11.9 Hz, 2H), 1.92-1.85 (m, 2H), 1.58-1.47(m, 2H), 1.21 (q, J=12.9, 11.8 Hz, 3H).

Example 23 Synthesis oftrans-6-chloro-N-(4-((2-(4-chloro-3-fluorophenoxy)ethyl)amino)cyclohexyl)quinoline-2-carboxamide

Step 1 Synthesis of trans-tert-butyl(4-(6-chloroquinoline-2-carboxamido)cyclohexyl)carbamate:

To a stirred mixture of 6-chloroquinoline-2-carboxylic acid (100 mg,0.48 mmol, 1 equiv) and trans-tert-butyl (4-aminocyclohexyl)carbamate(103 mg, 0.48 mmol, 1 equiv) in DMF (5 mL) was added HATU (365 mg, 0.96mmol, 2 equiv) and continued stir at RT for 30 min. DIPEA (0.3 ml, 1.44mmol, 3 equiv) was added and again stirred at RT for overnight. Reactionprogress was monitored by LCMS. After completion of reaction, thereaction mixture was poured into water (50 ml), the resulting yellowprecipitate was filtered off and again washed with water (20 mL×2). Theobtained solid was dried under vacuum to obtain trans-tert-butyl(4-(6-chloroquinoline-2-carboxamido)cyclohexyl)carbamate (120 mg,71.85%) as a yellow solid. LCMS: 404.6 [M+H]⁺

Step 2 Synthesis oftrans-N-(4-aminocyclohexyl)-6-chloroquinoline-2-carboxamidetrifluoroacetate salt:

To a stirred solution of trans-tert-butyl(4-(6-chloroquinoline-2-carboxamido)cyclohexyl)carbamate (120 mg, 0.297mmol, 1 equiv) in DCM (5 mL), was added TFA (0.5 mL) and the resultantreaction mixture was stirred at RT for overnight under nitrogenatmosphere. Reaction was monitored by LCMS. After completion ofreaction, the reaction mixture was concentrated under reduced pressureto obtain trans-N-(4-aminocyclohexyl)-6-chloroquinoline-2-carboxamidetrifluoroacetate salt (130 mg, quant. yield) as a light pink solid.LCMS: 304.4 [M+14]⁺

Step 3—Synthesis oftrans-6-chloro-N-(4-((2-(4-chloro-3-fluorophenoxy)ethyl)amino)cyclohexyl)quinoline-2-carboxamide:

To a stirred solution oftrans-N-(4-aminocyclohexyl)-6-chloroquinoline-2-carboxamidetrifluoroacetate salt (130 mg, 0.311 mmol, 1 equiv) in DMF (10 mL) wasadded K₂CO₃ (130 mg, 0.935 mmol, 3 equiv) and allowed to stir at RT for30 min. 4-(2-bromoethoxy)-1-chloro-2-fluorobenzene (80 mg, 0.311 mmol, 1equiv) was added and heated at 80° C. for overnight. Reaction progresswas monitored by LCMS. After completion of reaction, the reactionmixture was poured into ice cold water (50 m1) and extracted with EtOAc(2×30 mL). Combined organic layer washed with water (4×20 mL), brinesolution (1×20 mL), dried over anhydrous sodium sulfate and concentratedunder reduced pressure to obtain crude which was purified byreversed-phase HPLC to obtaintrans-6-chloro-N-(4-((2-(4-chloro-3-fluorophenoxy)ethyl)amino)cyclohexyl)quinoline-2-carboxamide(Compound 31—5 mg, 3.3%) as an off white solid. LCMS: 476.4 [M+H]⁺;¹HNMR (500 MHz, DMSO-d₆) δ 8.64 (d, J=8.5 Hz, 1H), 8.54 (d, J=8.6 Hz,1H), 8.39-8.33 (m, 2H), 8.25 (d, J=2.4 Hz, 1H), 8.17 (t, J=8.6 Hz, 2H),7.88 (dd, J=9.0, 2.4 Hz, 1H), 7.47 (t, J=8.9 Hz, 1H), 7.09 (dd, J=11.5,2.9 Hz, 1H), 6.85 (dd, J=8.8, 2.8 Hz, 1H), 4.04 (t, J=5.6 Hz, 2H), 3.81(dq, J=11.0,7.1, 6.1 Hz, 1H), 2.92 (t, J=5.6 Hz, 2H), 1.99-1.92 (m, 2H),1.87 (d, J=12.4 Hz, 2H), 1.56-1.47 (m, 2H), 1.23 (s, 1H), 1.18-1.09 (m,2H).

Example 24 Synthesis oftrans-5-chloro-N-(4-((2-(4-chloro-3-fluorophenoxy)ethyl)amino)cyclohexyl)benzofuran-2-carboxamide

Step 1—Synthesis of trans-tert-butylN-[4-[(5-chlorobenzofuran-2-carbonyl)amino]cyclohexyl]carbamate:

To a solution of 5-chlorobenzofuran-2-carboxylic acid (0.300 g, 1.53mmol, 1.0 equiv) in DMF (5 mL) was added HATU (0.872 g, 2.3 mmol, 1.5equiv) and trans-tert-butyl N-(4-aminocyclohexyl)carbamate (0.327 g,1.53 mmol, 1 equiv) followed by the addition of DIPEA (0.395 g, 3.06mmol, 2.0 equiv). The reaction mixture was allowed to stir at RT forovernight. Product formation was confirmed by LCMS. After completion ofreaction the reaction mixture was diluted with water and the resultingprecipitate was filtered off and the obtained crude product wascrystallized in MeOH to obtain trans-tert-butylN-[4-[(5-chlorobenzofuran-2-carbonyl)amino]cyclohexyl]carbamate (0.450g, 75% Yield) as an off-white solid. LCMS: 393.3 [M+H]⁺

Step 2—Synthesis oftrans-N-(4-aminocyclohexyl)-5-chlorobenzofuran-2-carboxamidetrifluoroacetate salt:

To a stirred solution of trans-tert-butylN-[4-[(5-chlorobenzofuran-2-carbonyl)amino]cyclohexyl]carbamate (0.450g, 1.15 mmol, 1.0 equiv) in DCM (10 mL), was added Trifluoroacetic acid(4 mL). The reaction mixture was allowed to stir at RT for 1 h. Productformation was confirmed by LCMS. After completion of reaction, thereaction mixture was concentrated under reduced pressure to obtaintrans-N-(4-aminocyclohexyl)-5-chlorobenzofuran-2-carboxamidetrifluoroacetate salt (0.450 g, Quant. Yield). LCMS: 292.3 [M+H]⁺

Step 3—Synthesis of 4-(2-bromoethoxy)-1-chloro-2-fluoro-benzene:

To a stirred solution 4-chloro-3-fluoro-phenol (1.00 g, 6.83 mmol, 1.0equiv) in EtOH (30 mL), was added K₂CO₃ (1.414 g, 10.25 mmol, 1.5equiv), followed by the addition of 1,2-dibromoethane (1.284 g, 6.83mmol, 1.0 equiv) and the mixture was allowed to stir at 80° C. forovernight. Product formation was confirmed by LCMS and TLC. Aftercompletion of reaction, reaction mixture was concentrated under reducedpressure. The residue was diluted with water and extracted with ethylacetate (50 mL×3). Combined organic layer was washed with brine (15 mL),dried over anhydrous Na₂SO₄ and concentrated. The crude product obtainedwas purified by flash chromatography (0-40% Ethyl acetate in hexane asan eluent) to obtain 4-(2-bromoethoxy)-1-chloro-2-fluoro-benzene (0.60g, 35% Yield). LCMS: 252.3 [M+H]⁺

Step 4—Synthesis oftrans-5-chloro-N-(4-((2-(4-chloro-3-fluorophenoxy)ethyl)amino)cyclohexyl)benzofuran-2-carboxamide:

To a stirred solution oftrans-N-(4-aminocyclohexyl)-5-chlorobenzofuran-2-carboxamidetrifluoroacetate salt (0.100 g, 0.25 mmol, 1.0 equiv) in DMF (3 mL), wasadded K₂CO₃ (0.053 g, 0.38 mmol, 1.5 equiv), followed by the addition of4-(2-bromoethoxy)-1-chloro-2-fluoro-benzene (0.063 g, 0.25 mmol, 1.0equiv) and the mixture was allowed to stir at 60° C. for overnight.Product formation was confirmed by LCMS and TLC. After completion ofreaction the mixture was concentrated under reduced pressure. Theresidue was diluted with water and extracted with ethyl acetate (30mL×3). Combined organic layer was washed with water (15 mL×6), driedover anhydrous Na₂SO₄ and concentrated. The crude product obtained waspurified by reverse phase HPLC to obtaintrans-5-chloro-N-(4-((2-(4-chloro-3-fluorophenoxy)ethyl)amino)cyclohexyl)benzofuran-2-carboxamide(Compound 32-8.6 mg, 7.5% Yield) as an off-white solid. LCMS: 465.3[M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 8.57 (d, J=8.1 Hz, 1H), 7.86 (d,J=2.3 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.52 (s, 1H), 7.46 (t, J=8.8 Hz,2H), 7.07 (dd, J=11.6, 2.8 Hz, 1H), 6.88-6.80 (m, 1H), 4.02 (t, J=5.4Hz, 2H), 3.81-3.67 (m, 1H), 2.90 (s, 2H), 1.98-1.90 (m, 2H), 1.87-1.79(m, 2H), 1.42 (q, J=12.8, 12.3 Hz, 2H), 1.23 (s, 1H), 1.10 (q, J=12.4Hz, 2H).

Example 25 Chiral Resolution oftrans-2-(4-chlorophenoxy)-N-((1r,4r)-4-(0-(4-chlorophenoxy)-2-hydroxypropyl)amino)cyclohexyl)acetamide

The enantiomers,(+)-2-(4-chlorophenoxy)-N-(4-((3-(4-chlorophenoxy)-2-hydroxypropyl)amino)cyclohexyl)acetamide(Compound 3—[α]_(D) ²⁰=12.47° (c=0.109, MeOH); elution time: 6.89 min)and(−)-2-(4-chlorophenoxy)-N-(4-((3-(4-chlorophenoxy)-2-hydroxypropyl)amino)cyclohexyl)acetamide(Compound 4—[α]_(D) ²⁰=−13.5° (c=0.0976, MeOH); elution time: 12.75min), were separated by chiral SFC (Daicel Chiralcel® OD-H, 250×4.6 mm,5 μm). Isocratic program with analytical grade liquid carbon dioxide andHPLC grade MeOH (0.2% DEA).

Example 26 Chiral Resolution oftrans-2-(4-chloro-3-fluorophenoxy)-N-(4-((3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)amino)cyclohexyl)acetamide

The enantiomers,(+)-2-(4-chloro-3-fluorophenoxy)-N-(4-((3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)amino)cyclohexyl)acetamide(Compound 6—[α]_(D) ²⁰=15.55° (c=0.1075, MeOH); elution time: 12.16 min)and(−)-2-(4-chloro-3-fluorophenoxy)-N-(4-((3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)amino)cyclohexyl)acetamide(Compound 7—[α]_(D) ²⁰=−8.41° (c=0.1067, MeOH); elution time: 16.97min), were separated by chiral SFC (Daicel Chiralcel® OD-H, 250×4.6 mm,5 μm). Isocratic program with analytical grade liquid carbon dioxide andHPLC grade MeOH (0.2% DEA). LCMS: 503 [M+1-1]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ7.92 (d, J=6.36 Hz, 2H), 7.37-7.57 (m, 2H), 7.06 (d, J=11.74Hz, 2H), 6.83 (m, 2H), 4.48 (s, 4H), 3.97 (m, 1H), 3.89 (d, J=6.85 Hz,1H), 3.80 (m, 1H), 3.55 (m, 3H), 1.85 (m, 1H), 1.77 (d, J=14.18 Hz, 3H),1.35 (br. s., 1H), 1.23 (br. s., 2H).

Example 27 Chiral Resolution of2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)-2-hydroxypropyl)piperidin-4-yl)acetamide

The enantiomers,(−)-2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)-2-hydroxypropyl)piperidin-4-yl)acetamide(Compound 15 elution time: 16.39) and(+)-2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)-2-hydroxypropyl)piperidin-4-yl)acetamide(Compound 16—[α]_(D) ²⁰=7.91° (c=0.1045, MeOH); elution time: 24.53min), were separated by chiral SFC (Daicel Chiralcel® AD-H, 250×4.6 mm,5 μm). Isocratic program with analytical grade liquid carbon dioxide andHPLC grade EtOH (0.2% DEA).

Example 28 Chiral Resolution of2-(4-chloro-3-fluorophenoxy)-N-(1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-4-yl)acetamide

The enantiomers(−)-2-(4-chloro-3-fluorophenoxy)-N-(1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-4-yl)acetamide(Compound 26—[α]_(D) ²⁰-7.23° (c=0.1098, MeOH); elution time: 9.15 min)and(+)-2-(4-chloro-3-fluorophenoxy)-N-(1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-4-yl)acetamide(Compound 27—[α]_(D) ²⁰ 7.84° (c=0.1012, MeOH); elution time: 12.52 min)were separated by chiral SFC (CHIRALPAK-AD-H, 250×20 mm, 5 μm).Isocratic Program with analytical grade liquid carbon dioxide and HPLCgrade EtOH (0.1% trifluoroacetic acid).

Example 29 Synthesis oftrans-6-chloro-N-(4-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclohexyl)-2-naphthamide

To a solution oftrans-N-(4-aminocyclohexyl)-2-(4-chloro-3-fluorophenoxy)acetamide2,2,2-trifluoroacetate (0.100 g, 0.241 mmol, 1.0 equiv) in DMF (5 mL)was added 6-chloro-2-naphthoic acid (0.050 g, 0.241 mmol, 1.0 equiv) andHATU (0.137 g, 0.36 mmol, 1.50 equiv) at RT. The reaction mixture wasstir for 10 min. DIPEA (0.5 mL) was added and the resultant reactionmixture was allowed to stir at RT overnight. Product formation wasconfirmed by LCMS. The reaction mixture was diluted with water (50 mL)and extracted with ethyl acetate (100 mL×2). Combined organic extractswere washed with water (50 mL×4), dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to obtain crude which wascrystallized in MeOH to obtaintrans-6-chloro-N-(4-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclohexyl)-2-naphthamide(Compound 145—60 mg, 51.28% Yield) as an off-white solid. LCMS: 489.3[M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ 8.57-8.37 (m, 2H), 8.11 (s, 1H),8.09-7.95 (m, 3H), 7.59 (d, J=8.8 Hz, 1H), 7.50 (t, J=9.0 Hz, 1H), 7.08(dd, J=2.6, 11.4 Hz, 1H), 6.86 (d, J=7.5 Hz, 1H), 4.52 (s, 2H), 3.81(br. s., 1H), 3.63 (br. s., 1H), 1.91 (br. s., 2H), 1.85 (br. s., 2H),1.53-1.29 (m, 4H).

Example 30 Synthesis of6-chloro-N-(1-(3-(4-chloro-3-fluorophenoxy)propyl)piperidin-4-yl)quinoline-2-carboxamide

To a stirred solution 6-chloro-N-(piperidin-4-yl)quinoline-2-carboxamide2,2,2-trifluoroacetate (0.100 g, 0.247 mmol, 1.0 equiv) in DMF (5 mL),was added K₂CO₃ (0.102 g, 0.742 mmol, 3.0 equiv), followed by theaddition of 4-(3-bromopropoxy)-1-chloro-2-fluorobenzene (0.072 g, 0.272mmol, 1.0 equiv) and the mixture was allowed to stir at 80° C. forovernight. Product formation was confirmed by LCMS. The reaction mixturewas diluted with water and extracted with ethyl acetate (30 mL×3).Combined organic extracts were washed with water (15 mL×4), dried overanhydrous Na₂SO₄ and concentrated. The crude product obtained waspurified by reverse phase HPLC to obtain6-chloro-N-(1-(3-(4-chloro-3-fluorophenoxy)propyl)piperidin-4-yl)quinoline-2-carboxamide(Compound 146—25 mg, 21% Yield) as an off-white solid. LCMS: 476.3[M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ 9.55 (br. s., 1H), 9.01 (d, J=7.5 Hz,1H), 8.55 (d, J=8.8 Hz, 1H), 8.27 (br. s., 1H), 8.19 (d, J=6.6 Hz, 1H),7.95-7.85 (m, 1H), 7.51 (t, J=9.0 Hz, 1H), 7.10 (d, J=11.4 Hz, 1H), 6.86(d, J=9.2 Hz, 1H), 4.11 (br. s., 2H), 3.60 (d, J=11.4 Hz, 2H), 3.27-3.07(m, 3H), 2.17 (br. s., 2H), 2.12-1.88 (m, 3H).

Example 31 Synthesis oftrans-5-chloro-N-(4-((3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)amino)cyclohexyl)benzofuran-2-carboxamide

To a stirred solutiontrans-N-(4-aminocyclohexyl)-5-chlorobenzofuran-2-carboxamide2,2,2-trifluoroacetate (0.250 g, 0.62 mmol, 1.0 equiv) in DMF (3 mL),was added K₂CO₃ (0.128 g, 0.93 mmol, 1.5 equiv), followed by theaddition of 2-[(4-chloro-3-fluoro-phenoxy)methyl]oxirane (0.125 g, 0.62mmol, 1.0 equiv) and the mixture was allowed to stir at 80° C. forovernight. Product formation was confirmed by LCMS. The reaction mixturewas diluted with water and extracted with ethyl acetate (30 mL×3).Combined organic extracts were washed with water (15 mL×4), dried overanhydrous Na₂SO₄ and concentrated. The crude product obtained waspurified by reverse phase HPLC to obtaintrans-5-chloro-N-(4-((3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)amino)cyclohexyl)benzofuran-2-carboxamide(Compound 147—35 mg, 11.5% Yield) as an off-white solid. LCMS 495.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.57 (d, J=8.1 Hz, 1H), 7.86 (d,J=2.2 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.54-7.41 (m, 3H), 7.08 (dd,J=11.3, 2.9 Hz, 1H), 6.84 (dd, J=8.7, 3.0 Hz, 1H), 4.01 (ddd, J=9.0,6.0, 3.7 Hz, 1H), 3.95-3.82 (m, 2H), 3.76 (dd, J=13.7, 7.7 Hz, 1H), 2.74(s, 1H), 1.94 (d, J=11.6 Hz, 2H), 1.84 (d, J=12.2 Hz, 2H), 1.41 (q,J=12.6 Hz, 2H), 1.23 (s, 1H), 1.14 (d, J=12.2 Hz, 2H).

Example 32 Synthesis of5-chloro-N-(1-(3-(4-chloro-3-fluorophenoxy)propyl)piperidin-4-yl)benzofuran-2-carboxamide

To a stirred solution5-chloro-N-(piperidin-4-yl)benzofuran-2-carboxamide hydrochloride (0.200g, 0.63 mmol, 1.0 equiv) in DMF (3 mL), was added K₂CO₃ (0.131 g, 0.95mmol, 1.5 equiv), followed by the addition of4-(3-bromopropoxy)-1-chloro-2-fluoro-benzene (0.168 g, 0.63 mmol, 1.0equiv) and the mixture was allowed to stir at 60° C. for overnight.Product formation was confirmed by LCMS. The reaction mixture wasdiluted with water and stirred at RT for 10 min and resulting solid wasfiltered off, washed with excess water. Obtained solid material wasdried under vacuum and washed with hexane to obtain5-chloro-N-(1-(3-(4-chloro-3-fluorophenoxy)propyl)piperidin-4-yl)benzofuran-2-carboxamide(Compound 148—180 mg, 61% Yield). LCMS 465.3 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ 8.62 (d, J=7.9 Hz, 1H), 7.86 (d, J=2.3 Hz, 1H), 7.69 (d,J=8.8 Hz, 1H), 7.52 (s, 1H), 7.46 (dd, J=11.3, 7.7 Hz, 2H), 7.06 (dd,J=11.6, 2.9 Hz, 1H), 6.83 (dd, J=8.9, 2.8 Hz, 1H), 4.03 (t, J=6.3 Hz,2H), 3.76 (dtd, J=13.8, 10.1, 9.6, 4.4 Hz, 1H), 2.88 (d, J=11.2 Hz, 2H),2.41 (t, J=7.1 Hz, 2H), 1.98 (t, J=11.5 Hz, 2H), 1.86 (p, J=6.6 Hz, 2H),1.81-1.72 (m, 2H), 1.61 (qd, J=12.1, 3.6 Hz, 2H), 1.24 (d, J=5.1 Hz,2H).

Example 33 Synthesis oftrans-2-(3-chloro-4-fluorophenoxy)-N-(4-(((6-chloroquinolin-2-yl)methyl)amino)cyclohexyl)acetamide

Step 1—Synthesis of 2-(bromomethyl)-6-chloroquinoline:

To a stirred solution of 6-chloro-2-methylquinoline (1.0 g, 5.6 mmol, 1equiv) in CCl₄(10 mL) was added NBS (1.1 g, 6.18 mmol, 1.1 equiv) andAIBN (0.10 g, 0.56 mmol, 0.1 equiv). The reaction mixture was heated at80° C. for 3 h. Progress of the reaction was monitored by TLC and LCMS.After completion of the reaction, the reaction mixture was diluted withaqueous solution of sodium bicarbonate (15 mL) and extracted with DCM(25 mL×3). Combined organic layer was washed with brine (40 mL), driedover anhydrous sodium sulfate and concentrated under reduced pressure.Crude product was purified by flash chromatography (0 to 50% ethylacetate in hexane as an eluent) to obtain2-(bromomethyl)-6-chloroquinoline (0.400 g). LCMS 255.9 [M+H]⁺

Step 2—Synthesis oftrans-2-(3-chloro-4-fluorophenoxy)-N-(4-(((6-chloroquinolin-2-yl)methyl)amino)cyclohexyl)acetamide:

To a stirred solution oftrans-N-(4-aminocyclohexyl)-2-(3-chloro-4-fluorophenoxy)acetamide2,2,2-trifluoroacetate (0.566 g, 1.37 mmol, 0.1 equiv), in DCM (10 mL)was TEA (0.212 g, 2.1 mmol, 1.5 equiv) followed by the addition of added2-(bromomethyl)-6-chloroquinoline (0.35 g, 1.37 mmol, 1 equiv). Thereaction mixture was allowed to stir at RT for 3 h. Progress of thereaction was monitored by LCMS. After completion of the reaction, thereaction mixture was diluted with water (20 mL) and extracted with DCM(25 mL×3). Combined organic layer was washed with water (15 mL×4), driedover anhydrous sodium sulfate and concentrated under reduced pressure.Crude compound was purified by reversed phase HPLC to obtaintrans-2-(3-chloro-4-fluorophenoxy)-N-(4-(((6-chloroquinolin-2-yl)methyl)amino)cyclohexyl)acetamide(Compound 151—0.040 g, 6% Yield) as an off-white solid. LCMS 476.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.30 (d, J=6.5 Hz, 1H), 8.09 (s,1H), 7.97 (s, 1H), 7.89 (d, J=7.9 Hz, 1H), 7.71 (t, J=12.6 Hz, 2H), 7.48(t, J=8.8 Hz, 1H), 7.05 (d, J=12.0 Hz, 1H), 6.83 (d, J=8.9 Hz, 1H), 4.48(s, 2H), 4.01 (s, 2H), 3.58 (d, J=10.4 Hz, 1H), 3.17 (s, 1H), 2.39 (s,2H), 1.93 (dd, J=16.3, 10.2 Hz, 2H), 1.76 (d, J=12.3 Hz, 2H), 1.28-1.09(m, 5H).

Example 34 Synthesis oftrans-6-chloro-N-(4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide

To a solution of 2-((5-chloropyridin-2-yl)oxy)acetic acid (1.0 g, 4.67mmol, 1.0 equiv) in DMF (10 mL) was added DIPEA (2.5 mL, 14.01 mmol, 3.0equiv) followed by the addition of HATU (3.5 g, 9.34 mmol, 3.0 equiv).The resulting mixture was stirred for 30 min.trans-N-(4-aminocyclohexyl)-2-(4-chlorophenoxy)acetamide2,2,2-trifluoroacetate (1.7 g, 4.67 mmol, 2.0 equiv) was added and thereaction mixture was allowed to stir overnight at RT. The resultingprecipitate was filtered off and washed with excess methanol to obtaintrans-6-chloro-N-(4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide(Compound 156-700 mg, 31% Yield) as an off-white solid. LCMS 478 [M+H]⁺;¹H NMR (400 MHz,DMSO-d₆) δ 7.94 (d, J=7.9 Hz, 1H), 7.82 (d, J=7.9 Hz,1H), 7.39-7.25 (m, J=8.8 Hz, 2H), 7.03-6.88 (m, J=8.8 Hz, 2H), 6.78 (d,J=8.3 Hz, 1H), 6.59 (s, 1H), 6.50 (d, J=8.3 Hz, 1H), 6.18 (br. s., 1H),4.50-4.37 (m, 3H), 3.57 (br. s., 2H), 3.44 (d, J=11.8 Hz, 1H), 3.22-3.10(m, 1H), 1.76 (br. s., 4H), 1.34 (d, J=9.2 Hz, 4H).

Example 35 Chiral Resolution of5-chloro-N-(1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-4-yl)benzofuran-2-carboxamide

The enantiomers,(+)-5-chloro-N-(1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-4-yl)benzofuran-2-carboxamide(Compound 149—[α]_(D) ²⁰=−13.09 (c=0.1016 w/v %, MeOH); elution time:15.61 min) and(−)-5-chloro-N-(1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-4-yl)benzofuran-2-carboxamide(Compound 150 —[α]_(D) ²⁰=+13.16 (c=0.1006 w/v %, MeOH); elution time:17.32 min), were separated by chiral SFC (Daicel Chiralcel® OD-H,250×4.6 mm, 5 μm). Isocratic program with analytical grade liquid carbondioxide and HPLC grade MeOH (0.2% DEA).

Example 36 Chiral Resolution of6-chloro-N-(1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-4-yl)quinoline-2-carboxamide

The enantiomers,(+)-6-chloro-N-(1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-4-yl)quinoline-2-carboxamide(Compound 152—[α]_(D) ²⁰=−95.75 (c=0.1036, w/v %, MeOH); elution time:22.17 min) and(−)-6-chloro-N-(1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-4-yl)quinoline-2-carboxamide(Compound 153 —[α]_(D) ²⁰=+113.73 (c=0.1016, w/v %, MeOH); elution time:27.55 min), were separated by chiral SFC (Chiralpak AD-H, 250×4.6 mm, 5μm). Isocratic Program with analytical grade liquid carbon dioxide andHPLC grade EtOH (0.2% DEA).

Example 37 Chiral Resolution oftrans-5-chloro-N-(4-((3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)amino)cyclohexyl)benzofuran-2-carboxamide

The enantiomers,(+)-trans-5-chloro-N-(4-((3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)amino)cyclohexyl)benzofuran-2-carboxamide(Compound 154—[α]_(D) ²⁰=+13.91 (c=0.1049, w/v %, MeOH); elution time:11.77 min) and(−)-trans-5-chloro-N-(4-((3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)amino)cyclohexyl)benzofuran-2-carboxamide(Compound 155—[α]_(D) ²⁰=−12.46 (c=0.1011 w/v %, MeOH); elution time:18.08 min), were separated by chiral SFC (Daicel Chiralcel® OD-H,250×4.6 mm, 5 μm). Isocratic Program with analytical grade liquid carbondioxide and HPLC grade MeOH (0.2% DEA).

Example 38 Chiral Resolution oftrans-6-chloro-N-(4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide

The enantiomers,(+)-trans-6-chloro-N-(4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide(Compound 158—[α]_(D) ²⁰=+26.68 (c=0.053, w/v %, MeOH); elution time:11.45 min) and(−)-trans-6-chloro-N-(4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide(Compound 157—[α]_(D) ²⁰=−15.97 (c=0.063 w/v %, MeOH); elution time:10.09 min), were separated by chiral SFC (Daicel Chiralcel® OD-H, 250×20mm, 5 μm). Isocratic Program with analytical grade liquid carbon dioxideand HPLC grade iPrOH (0.2% DEA).

Example 39 Synthesis oftrans-2-(4-chlorophenoxy)-N-(4-(5-((4-chlorophenoxy)methyl)-2-oxooxazolidin-3-yl)cyclohexyl)acetamide

To a stirred solution oftrans-2-(4-chlorophenoxy)-N-(4-((3-(4-chlorophenoxy)-2-hydroxypropyl)amino)cyclohexyl)acetamide(100 mg, 0.21 mmol, 1 equiv) in DCM (5 mL), was added Et₃N (0.2 mL, 1.1mmol, 5 equiv). The mixture was allowed to stir for 15 min. undernitrogen atmosphere. Isoindoline (26 mg, 1.05 mmol, 5 equiv) was addedto the mixture and the reaction mixture was cooled to 0° C. Phosgene(20% in toluene, 1 mL) was added to the mixture dropwise. Thetemperature was allowed to rise to RT and the reaction mixture stirredovernight at RT. Progress of the reaction was monitored by LCMS. Aftercompletion of the reaction, the reaction mixture was diluted with water(30 mL) and extracted with DCM (50 mL×2). The organic layer was washedwith water (50 mL), brine solution (50 mL). The organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure toobtain a crude compound, which was purified by reversed phase HPLC toobtaintrans-2-(4-chlorophenoxy)-N-(4-(5-((4-chlorophenoxy)methyl)-2-oxooxazolidin-3-yl)cyclohexyl)acetamide(Compound 159—25 mg, 24% Yield) as a white solid. LCMS 493.2 [M+H]⁺;¹HNMR (400 MHz, DMSO-d₆) δ 7.97 (d, J=8.0 Hz, 1H), 7.34 (d, J=8.4 Hz,4H), 7.01-6.93 (m, 4H), 4.84 (h, J=4.5 Hz, 1H), 4.45 (s, 2H), 4.18 (dd,J=10.9, 3.2 Hz, 1H), 4.08 (dd, J=10.9, 5.2 Hz, 1H), 3.64 (t, J=8.9 Hz,2H), 3.54-3.42 (m, 1H), 3.37 (dd, J=8.7, 5.9 Hz, 1H), 1.86-1.77 (m, 2H),1.74-1.66 (m, 2H), 1.57 (q, J=12.7, 12.3 Hz, 2H), 1.38 (tt, J=13.1, 6.5Hz, 2H).

BIOLOGICAL EXAMPLES Example B1—ATF4 Expression Inhibition Assay

HEK293T cells were maintained at 37° C. and 5% CO₂ in Dulbecco'sModified Eagle's Media (DMEM) supplemented with 10% fetal bovine serum(FBS), 2 mM L-glutamine, 100 U/ml penicillin, and 100 μg/mlstreptomycin. After reaching 80% of confluence, cells were detached andseeded on 6 well plates in complete media, allowed to recover overnightand treated for 3 hours with 100 nM thapsigargin (Tg) in the presence of100 nM or 1 μM concentration of a test compound (percent inhibitionassays) or various concentrations ranging from 1 nM to 1 μM (IC₅₀assay). Cells without treatment or cells treated with Tg alone were usedas controls.

After 3 hours of treatment with Tg and the test compound, cells werelysed with SDS-PAGE lysis buffer. Lysates were transferred to 1.5 mltubes and sonicated for 3 min, and total protein amounts were quantifiedusing BCA Protein Assay Kit (Pierce). Equal amount of proteins wereloaded on SDS-PAGE gels. Proteins were transferred onto 0.2 μm PVDFmembranes (BioRad) and probed with primary antibodies diluted inTris-buffered saline supplemented with 0.1% Tween 20 and 3% bovine serumalbumin.

ATF4 (11815) antibody was used as primary antibody (Cell SignalingTechnologies). A horseradish peroxidase (HRP)-conjugated secondaryantibody (Rockland) was employed to detect immune-reactive bands usingenhanced chemiluminescence (ECL Western Blotting Substrate, Pierce).Quantification of protein bands was done by densitometry using ImageJ.

Percentages of ATF4 inhibition after induction with Tg in the presenceof 100 nM or 1 μM of certain test compounds are shown in Table 2 andFIG. 1 . Percentage of ATF4 inhibition was calculated as the percentreduction normalized to Tg treatment (0% inhibition) and untreated cells(100% inhibition). Also shown in Table 2 is the calculated IC₅₀ for thetest compounds. Under ISR stressed conditions (resulting from treatmentwith Tg), ATF4 expression is generally upregulated. Accordingly,inhibition of ATF4 expression as a result of the test compound indicatessuppression of the ISR pathway.

TABLE 2 % ATF4 ATF4 inhibition Compound inhibition % ATF4 inhibitionIC₅₀ No. at 100 nM at 1 μM (nM) 1 0 71 353.1 2 40 56 162.9 3 35 77 145 431 54 n.d. 5 42 94 169.7 6 52 83 82.82 7 0 0 n.d. 8 0 0 n.d. 9 12 20n.d. 10 0 11 n.d. 11 0 0 n.d. 12 0 0 n.d. 13 57 93 57.22 14 0 0 n.d. 1577 99 52.14 16 0 38 n.d. 17 95 98 9.52 18 96 98 34.14 19 94 100 n.d. 2014 64 n.d. 21 54 78 n.d. 22 21 81 102.7 23 97 99 2.1 24 18 54 n.d. 25 00 n.d. 26 91 97 26.96 27 54 73 n.d. 28 88 97 25.83 29 87 95 51.81 30 3535 >3,000 31 41 93 n.d. 32 38 78 n.d. 145 97 97 17.05 146 88 100 49.93147 95 100 33.09 148 30 90 n.d. 149 62 96 29.85 150 0 43 n.d. 151 10 6790.72 152 86 91 49.02 153 0 0 n.d. 154 92 96 13.68 155 60 75 n.d. 156 9497 15.98 157 96 100 23.8 158 96 96 9.1 159 52 84 <100

Example B2—Protein Translation Assay

CHO cells were maintained at 37° C. and 5% CO₂ in DMEM supplemented with10% fetal bovine serum (FBS), 2 mM L-glutamine, 100 U/ml penicillin, and100 μg/ml streptomycin. After reaching 80% of confluence, cells weredetached and seeded on 6 well plates in complete media, allowed torecover overnight and treated for 2 hours with 1 μM of the test compound(to assess protein synthesis levels in unstressed condition), or for 1hour with 100 nM and 1 μM of the test compound and then co-treated with300 nM Tg and 100 nM and 1 μM of the test compound (to assess therecovery of protein synthesis in a stressed condition). Cells treatedwith Tg alone were used as controls.

After the 2 hours treatments, media were replaced by adding 10 μg/mlpuromycin (Sigma Aldrich) in complete media for 30 min. Media wereremoved and cells were lysed with SDS-PAGE lysis buffer. Lysates weretransferred to 1.5 ml tubes and sonicated for 3 minutes and totalprotein amount were quantified using BCA Protein Assay Kit (Pierce).Equal amount of protein (30 μg) was loaded on SDS-PAGE gels. Proteinswere transferred onto 0.2 μm PVDF membranes (BioRad) and probed withprimary antibodies diluted in Tris-buffered saline supplemented with0.1% Tween 20 and 3% bovine serum albumin.

Puromycin (121310) antibody was used as primary antibody (MerckMillipore). A HRP-conjugated secondary antibody (Rockland) was employedto detect immune-reactive bands using enhanced chemiluminescence (ECLWestern Blotting Substrate, Pierce). Quantification of protein bands wasdone by densitometry using ImageJ.

Percent increase of protein synthesis in unstressed cells (without Tgtreatment) in the presence of media alone or certain test compounds isshown in Table 3 and FIG. 2 . The percentage levels were normalized tothe media alone condition, which correspond to 100% protein synthesis.All compounds stimulated protein synthesis above baseline, indicatingthat the test compounds result in increased protein synthesis inunstressed cells.

Percent recovery of protein synthesis in stressed cells (with Tgtreatment) due to the test compounds at 100 nM or 1 μM is shown in FIGS.3A and 3B, respectively, and in Table 3. The levels were normalized tothe media alone and to Tg alone conditions, which correspond to 100% and0% respectively.

TABLE 3 % Recovery of % Recovery of protein protein expressionexpression % Protein expression Compound (100 nM test (1 μM testrelative to untreated No. compound) compound) (1 μM test compound) 163.8 160.3 151.7 2 42.5 135.2 136.2 3 69.4 154.7 161.5 5 64.9 189.1130.2 6 60.2 196.8 194.9 10 30.6 126.7 n.d. 13 49.6 159.2 94.0 15 35.6159.2 68.3 17 87.0 172.5 93.2 18 38.0 138.0 107.0 19 14.1 115.5 n.d. 2038.6 93.9 n.d. 21 70.5 182.0 n.d. 22 67.3 264.2 170.1 23 79.2 175.7119.6 24 11.8 24.34 n.d. 25 11.4 22.9 n.d. 26 34.2 175.7 111.8 28 38.0170.3 99.3 29 48.4 266.7 185.7 30 23.1 181.5 205.9 31 25.0 287.7 243.432 37.7 233.8 137.2 145 22.6 40.6 95.4 146 43.4 264.8 245.6 147 75.2261.5 189.5 148 37.2 250.2 123.2 149 107.3 281.2 138.4 150 61.0 199.5183.9 151 61.8 217.4 164.3 152 99.1 279.5 239.1 153 51.5 235.6 322.8 15496.3 234.5 188.3 155 68.5 190.3 262.6 156 25.1 199.8 197.1 157 39.7 97.3117.9 158 86.8 198.7 167.9 159 23.9 79.4 n.d.

Data summarized in Tables 2 and 3 show that some compounds havedifferential activity in ATF4 inhibition and protein synthesis underISR-inducing conditions. That is, some compounds are able to effectivelyinhibit ATF4 expression but do not restore protein synthesis. Othercompounds effectively restore protein synthesis but do not inhibit ATF4expression under ISR-inducing conditions. Still other compounds inhibitATF4 expression and restore protein synthesis. Certain compounds (suchas compounds 30, 150, 153) show increased protein translation withlimited (less than 50%) ATF4 inhibition. FIG. 3C shows percent ATF4inhibition (see Example B1) for select compounds against percentrecovery of protein synthesis. This differential modulation ofactivities represents a unique characteristic that can be exploited whenselecting specific compounds for a desired use.

Example B3—ATF4 Inhibition Assay Under all Stimulation

Chinese hamster ovary (CHO) cells that stably express human APP751incorporating the familial Alzheimer's disease mutation V717F were usedas a source of Aβ monomer and low-n oligomers. These cells, referred toas 7PA2 CHO cells, were cultured in 100 mm dishes with Dulbecco'smodified Eagle's medium (DMEM) containing 10% fetal bovine serum, 2 mML-glutamine, 100 U/ml penicillin, and 100 μg/ml penicillin, streptomycinand 200 μg/ml G418. Upon reaching 90-100% confluency, cells were washedwith 5 mL of glutamine- and serum-free DMEM and incubated forapproximately 16 h in 5 mL of the same DMEM. Conditioned media (CM) wascollected.

SH-SY5Y cells were maintained at 37° C. and 5% CO₂ in RPMI 1640 mediasupplemented with 10% fetal bovine serum (FBS), penicillin andstreptomycin. After reaching 80% of confluence, cells were detached andseeded on 6 well plates in complete media, allowed to recover 48 h andtreated for 16 hours with CM from WT CHO cells or 7PA2 CHO cells in thepresences of 1 μM of test compounds 3, 6, 15, 17, 23, 149, 152, or 153.

After 16 hours treatment, culture media were removed and cells werelysed with SDS-PAGE lysis buffer. Lysates were transferred to 1.5 mltubes and sonicated for 3 min. Total protein amount were quantifiedusing BCA Protein Assay Kit (Pierce). Equal amount of proteins (30 μg)was loaded on SDS-PAGE gels. Proteins were transferred onto 0.2 μm PVDFmembranes (BioRad) and probed with primary antibodies diluted inTris-buffered saline supplemented with 0.1% Tween 20 and 3% bovine serumalbumin.

ATF4 (11815) antibody was used as primary antibody (Cell SignalingTechnologies). A β-actin antibody was used as a control primaryantibody. An HRP-conjugated secondary antibody (Rockland) was employedto detect immune-reactive bands using enhanced chemiluminescence (ECLWestern Blotting Substrate, Pierce). Quantification of protein bands wasdone by densitometry using ImageJ.

Representative levels of ATF4 expression from the treatment with CM fromWT CHO cells (wtCM) or 7PA2 CHO cells (7PA2CM) are shown in FIG. 4A. Thelevels were normalized to β-actin expression and fold change wascalculated as the levels relative to the ATF4 expression level fromwtCM-treated SH-SY5Y cells (normalized to 1).

Percent inhibition of ATF4 expression in SH-SY5Y cells after incubationwith CM from the 7PA2 CHO cells as a result of the test compounds isshown in FIG. 4B. Percentage of ATF4 inhibition was calculated as thepercent reduction normalized to CM from 7PA2 CHO cells treatment (0%inhibition) and CM from WT CHO cells treatment (100% inhibition).

Example B4—Electrophysiology and Long-Term Potentiation

Hippocampal slices were prepared as described in Ardiles et al.,Pannexin 1 regulates bidirectional hippocampal synaptic plasticity inadult mice. Front Cell Neurosci, vol. 8, art. 326 (2014). Six toeleven-month-old WT C₅₇BL/6 or transgenic APP/PS1 mice (Jackson Lab34829-JAX) were deeply anesthetized with isoflurane and their brainswere quickly removed. 5-10 slices (350 pin) from each animal weredissected in ice-cold dissection buffer using a vibratome (LeicaVT1200S, Leica Microsystems, Nussloch, Germany). Slices were incubatedwith 5 μM ISRIB, 5 μM compound 3, 1 μM compound 152, or a vehicle(complete medium containing 0.1% DMSO) 20 min before conditioningstimulation. Synaptic responses were evoked by stimulating the Schaffercollaterals with 0.2 ms pulses delivered through concentric bipolarstimulating electrodes, and recorded extracellularly in the stratumradiatum of the CA1 subfield. Long-term potentiation (LTP) was inducedby four-theta burst stimulation (TBS) (10 trains of four pulses at 100Hz; 5 Hz inter-burst interval) delivered at 0.1 Hz. LTP magnitude basedon field excitatory postsynaptic potential (fEPSP) was calculated as theaverage (normalized to baseline) of the responses recorded 60 min afterconditioning stimulation. Similar experiments can be performed using adifferent test compound in place of ISRIB, compound 3, or compound 152.

Results for ISRIB are shown in FIG. 5A. Treatment of the slices fromboth the WT C₅₇BL/6 and APP/PS1 mice treated with the vehicle (emptycircles and empty triangles, respectively) resulted in LTP 60 minutesafter stimulation, with the APP/PS1 sample showing significantly reducedLTP. Treatment of the slices from the APP/PS1 mouse with ISRIB (blacktriangles), however, resulted in partial LTP recovery (FIG. 5A). FIG. 5Bshows the responses recorded in the last 10 minutes after conditioningstimulation of the slices from the WT C₅₇BL/6 and APP/PS1 mice treatedwith ISRIB (APP+ISRIB), and from APP/PS1 mice treated with compound 3(APP+Cmp3), or compound 152 (APP+Cmp152), or the vehicle (APP).

Example B5—Learning Memory in Aged Mice

Wild type 19-month old male C57B1/6J mice were used in an 8-arm radialwater maze (RAWM) to measure the hippocampal-mediated learning memory.The maze involved a pool 118.5 cm in diameter and 25 cm high with 8arms, each 41 cm in length, and an escape platform that could be moved.The pool was filled with water that was rendered opaque by adding whitepaint (Crayola, 54-2128-053). The escape platform remains hidden duringthe experiment. Visual cues were placed around the room such that theywere visible to animals exploring the maze.

9 mice were intraperitoneally injected with 5 mg/kg of compound 3formulated in 50% Polyethylene glycol (PEG-400) in distilled water andother 9 animals were intraperitoneally injected with the vehicle 50%PEG-400 in distilled water as a control group. Animals ran 6 trials aday for two days. Animals were allowed 1 minute to locate the escapeplatform. On successfully finding the platform, animals remained therefor 10 seconds before being returned to their holding cage. On a failedtrial, animals were guided to the escape platform and then returned totheir holding cage 10 seconds later.

Behavioral tests were recorded and scored using a video tracking andanalysis setup (Ethovision XT 8.5, Noldus Information Technology). Theprogram automatically analyzed the number of incorrect arm entries(termed number of errors) made per trial. Last three trials wereaveraged to determine learning memory after training.

At the end of the behavioral test, animals were sacrificed and thehippocampi were extracted and immediately frozen in liquid nitrogen andthen stored at −80° C. The frozen samples were then homogenized with a T10 basic ULTRA-TURRAX (IKa) in ice-cold buffer lysis (Cell Signaling9803) and protease and phosphatase inhibitors (Roche). Lysates weresonicated for 3 minutes and centrifuged at 13,000 rpm for 20 minutes at4° C. Protein concentration in supernatants was determined using BCAProtein Assay Kit (Pierce). Equal amount of proteins was loaded onSDS-PAGE gels. Proteins were transferred onto 0.2 μm PVDF membranes(BioRad) and probed with primary antibodies diluted in Tris-bufferedsaline supplemented with 0.1% Tween 20 and 3% bovine serum albumin.

ATF4 (11815) antibody (Cell Signaling Technologies) and β-actin(Sigma-Aldrich) antibodies were used as primary antibodies. AHRP-conjugated secondary antibody (Rockland) was employed to detectimmune-reactive bands using enhanced chemiluminescence (ECL WesternBlotting Substrate, Pierce). Quantification of protein bands was done bydensitometry using ImageJ software.

Results of RAWM task are shown in FIG. 6A. Aged animals with vehicleprogressively learned the location of the escape platform during thetrials. Interestingly, aged animals with compound 3 performed betterthan vehicle-treated animals suggesting an enhanced learning memory.Levels of ATF4 expression normalized to β-actin expression in hippocampiare shown in FIG. 6B, with individual data points being shown in FIG.6C. Animals that received compound 3 showed lower levels of ATF4expression compared with vehicle-treated animals. There is a clear trendindicating that the ISR pathway is being inhibited and a betterperformance in a learning memory task.

Example B6—Learning Memory, Long-Term Memory and Social Behavior afterTraumatic Brain Injury (TBI)

Wild type three-month-old male C57B1/6J mice were randomly assigned toTBI or sham surgeries. Animals were anesthetized and maintained at 2%isoflurane and secured to a stereotaxic frame with nontraumatic earbars. The hair on their scalp was removed, and eye ointment and betadinewere applied to their eyes and scalp, respectively. A midline incisionwas made to expose the skull. A unilateral TBI was induced in the rightparietal lobe using the controlled cortical impact model (Nat Neurosci.2014 August; 17(8): 1073-82). Mice received a 3.5-mm diametercraniectomy, a removal of part of the skull, using an electricmicrodrill. The coordinates of the craniectomy were: anteroposterior,2.00 mm and mediolateral, +2.00 mm with respect to bregma. After thecraniectomy, the contusion was induced using a 3-mm convex tip attachedto an electromagnetic impactor (Leica). The contusion depth was set to0.95 mm from dura with a velocity of 4.0 m/s sustained for 300 ms. Theseinjury parameters were chosen to target, but not penetrate, thehippocampus. Sham animals received craniectomy surgeries but without thefocal injury. After focal TBI surgery, the scalp was sutured and theanimal was allowed to recover in an incubation chamber set to 37° C.Animals were returned to their home cage after showing normal walkingand grooming behavior. All animals fully recovered from the surgicalprocedures as exhibited by normal behavior and weight maintenancemonitored throughout the duration of the experiments.

After 28 days post injury (dpi), animals were tested on the RAWM assay(see above). Animals ran 12 trials during learning test and 4 trialsduring memory test. Last three trials from learning test and all fourtrials from memory test were averaged to determine learning memory(learning test) and long-term memory (memory test).

Animals were intraperitoneally injected with 5 mg/kg of compound 3formulated in 50% PEG-400 in distilled water (n=10) or vehicle (50%PEG-400 in distilled water; n=10 for TBI group and n=8 for sham group)starting the day prior to behavior tests (27 dpi), after each of thefinal trials of the learning-test days (28 and 29 dpi) and before thesocial behavior test (42 dpi, see below) for a total of four injections.No injections were given when long-term memory was tested on day 35 dpi.

To quantitate social tendencies of the treated mice, the time spent witha novel conspecific mouse was measured in a Crawley's three-chamber box(J Vis Exp. 2011; (48): 2473). Treated animals were left to explore allthree empty chambers freely for 10 minutes for habituation. Social pairmouse was placed in the housing cage at one side of the apparatus andtreated animals in opposite chamber so that the mouse can freely explorethe entire apparatus for 10 minutes. The time spent with thenever-before-met animal was recorded. Direct contact between the treatedmouse and the housing cage or stretching of the body of the subjectmouse in an area 3-5 cm around the housing cage is counted as an activecontact.

Learning memory and long-term memory after TBI in mice are shown inFIGS. 7A and 7B respectively. Compared with vehicle-treated animals(squares), compound 3-treated animals (triangles) made significantlyless errors over the course of training (FIG. 7A) and a similar trendwas seen when memory was tested 7 days (35 dpi) after training (FIG.7B).

Social behavior results are shown in FIG. 7C. Vehicle-treatedTBI-injured animals spent significantly less time in the compartmentwith the novel animal compared to vehicle-treated animals from shamgroup indicating impairment in sociability. Interestingly, compound3-treated TBI-injured animals spent more time with the novel mouse atlevels similar to those animals from sham group indicating normalsociability, social motivation and affiliation. Individual values andmean±SEM are shown in FIG. 7C. Statistical analyses were performed usingGraphPad Prism software and significant difference was assessed by ttest (*<0.05, **<0.01, and ***<0.001).

Example B7—Fasting-Induced Muscle Atrophy

Wild type eight-weeks-old male Ba1b/c mice obtained from the vivariumFundación Ciencia & Vida Chile (Santiago, Chile) were used. Mice werehoused in independent plastic cages in a room maintained at 25° C. witha 12-h:12-h light:dark cycle.

Twenty-four hours before and during the 2 days of fasted procedures,animals received oral administration via feeding tubes (15 gauge) ofvehicle (50% Polyethylene glycol 400 (Sigma-Aldrich P3265) in distilledwater or 10 mg/kg of compound 3 formulated in vehicle solution.

After 2 days of fasting the animals were sacrificed and muscles wereremoved from both hindlimbs. Mice with feed and water ad libitum wereused as control.

For in vivo measurements of protein synthesis, puromycin (Sigma-Aldrich,P8833) was prepared at 0.04 μmol/g body weight in a volume of 200 μL ofPBS, and subsequently administered into the animals via IP injection, 30min prior to muscle collection.

Upon collection, muscles were immediately frozen in liquid nitrogen andthen stored at 80° C. The frozen muscles were then homogenized with a T10 basic ULTRA-TURRAX (IKa) in ice-cold buffer lysis (Cell Signaling9803) and protease and phosphatase inhibitors (Roche). Lysates weresonicated for 3 min and centrifuged at 13,000 rpm for 20 minutes at 4°C. Protein concentration in supernatants was determined using BCAProtein Assay Kit (Pierce). Equal amount of proteins was loaded onSDS-PAGE gels. Proteins were transferred onto 0.2 um PVDF membranes(BioRad) and probed with primary antibodies diluted in Tris-bufferedsaline supplemented with 0.1% Tween 20 and 3% bovine serum albumin.

Puromycin (12D10) (Merck Millipore) and β-actin (Sigma-Aldrich)antibodies were used as primary antibodies. A HRP-conjugated secondaryantibody (Rockland) was employed to detect immune-reactive bands usingenhanced chemiluminescence (ECL Western Blotting Substrate, Pierce).Quantification of protein bands was done by densitometry using ImageJsoftware.

For immunohistochemical analysis of cross-sectional area (CSA), musclesfrom control (Fed) and fasted animals were submerged individually inoptimal cutting temperature (OCT) compound (Tissue-Tek; Sakura) atresting length, and frozen in isopentane cooled with liquid nitrogen.Cross-sections (10-μm thick) from the mid-belly of the muscles wereobtained with a cryostat (Leica) and immunostained with puromycinantibody (12D10) (Merck Millipore). A HRP-polymer conjugated secondaryantibody (Biocare Medical, MM620L) followed by diaminobenzidinesubstrate incubation (ImmPACT DAB—Vector, SK-4105) were employed todetect puromycinylated structures in CSA.

Percent of protein synthesis in fasted muscles is shown in FIG. 8A forcompound 3 and the vehicle control. The levels were normalized toβ-actin expression and percentage was calculated as the percent relativeto protein synthesis levels from control mice (Fed) which correspond to100%.

Muscle fiber CSA were visualized with a Zeiss Axio Lab.A1 microscope andan Axiocam (Zeiss) digital camera. Puromycin staining in CSA is shown inFIG. 8B for compound 3. Muscle sections from control mice (fed) showsfibers stained with puromycin indicating de novo protein synthesis. Nostaining was detected in vehicle-treated fasted mice indicating asignificant reduction of protein synthesis. Fasted mice treated withcompound 3, however, showed a partial staining in muscle fibersindicating a partial recovery of protein synthesis as seen in FIG. 8A.

Gastrocnemius weight from control (fed) and fasted animals treated withcompound 3 or compound 152 are shown in FIG. 9A and FIG. 9Brespectively. Percent of protein synthesis from control (fed) or fastedanimals treated with compound 3 or compound 152 are shown in FIG. 9C andFIG. 9D respectively. The levels were normalized to β-actin expressionand percentage was calculated as the percent relative to proteinsynthesis levels from control mice (fed) which correspond to 100%.Atrogin-1 expression in gastrocnemius from control (fed) and fastedanimals treated with compound 3 or compound 152 are shown in FIG. 9E andFIG. 9F respectively. The levels were normalized to β-actin expressionand fold change was calculated as the levels relative to the expressionlevels from control mice (fed) which corresponds to 1. Data was shown asindividual values and mean±standard error of mean (SEM). Statisticalanalyses were performed using GraphPad Prism software and significantdifference was assessed by t test (*<0.05, **<0.01, ***<0.001).

Muscle fiber CSAs were visualized with a Zeiss Axio Lab.A1 microscopeand an Axiocam (Zeiss) digital camera. ATF4 staining in CSA is shown inFIG. 9G. Histological muscle sections from fasted mice treated withvehicle show fibers containing positive ATF4 staining, indicating theactivation of the ISR. No staining was detected in control (fed) or infasted mice treated with compound 152, indicating a complete inhibitionof the ISR pathways in the muscle of these animals.

Example B8—Immobilization-Induced Muscle Atrophy

Wild type eight-weeks-old male Ba1b/c mice obtained from the vivariumFundación Ciencia & Vida Chile (Santiago, Chile) were used. Mice werehoused in independent plastic cages, fed ad libitum in a room maintainedat 25° C. with a 12-h:12-h light:dark cycle.

Twenty-four hours before and during the 3 days of immobilizationprocedures, animals received oral administration via feeding tubes (15gauge) of vehicle (50% Polyethylene glycol 400 (Sigma-Aldrich P3265) indistilled water or 10 mg/kg of compound 3 formulated in vehicle.

One hindlimb was immobilized with a plastic stick placed over and underthe limb and fixed with a medical adhesive bandage. Animals were dailymonitored. The immobilization procedure prevented movement of theimmobilized leg alone. After 3 days, the animals were sacrificed andgastrocnemius, quadriceps and tibialis anterior muscles were removedfrom both hindlimbs, the contralateral, non-immobilized leg being usedas an internal control.

For in vivo measurements of protein synthesis, puromycin (Sigma-Aldrich,P8833) was prepared at 0.04 μmol/g body weight in a volume of 200 μL ofPBS, and subsequently administered into the animals via intraperitonealinjection, 30 min prior to muscle collection.

Upon collection, muscles were immediately frozen in liquid nitrogen andthen stored at −80° C. The frozen muscles were then homogenized with a T10 basic ULTRA-TURRAX (IKa) in ice-cold buffer lysis (Cell Signaling9803) and protease and phosphatase inhibitors (Roche). Lysates weresonicated for 3 min and centrifuged at 13,000 rpm for 20 minutes at 4°C. Protein concentration in supernatants was determined using BCAProtein Assay Kit (Pierce). Equal amount of proteins was loaded onSDS-PAGE gels. Proteins were transferred onto 0.2 um PVDF membranes(BioRad) and probed with primary antibodies diluted in Tris-bufferedsaline supplemented with 0.1% Tween 20 and 3% bovine serum albumin.

Puromycin (12D10) (Merck Millipore) and β-actin (Sigma-Aldrich)antibodies were used as primary antibodies. A HRP-conjugated secondaryantibody (Rockland) was employed to detect immune-reactive bands usingenhanced chemiluminescence (ECL Western Blotting Substrate, Pierce).Quantification of protein bands was done by densitometry using ImageJsoftware.

Percent of protein synthesis in mobile and immobile hind limbs sectionsfrom gastrocnemius, tibialis anterior, and quadriceps are shown in FIGS.10A, 10B and 10C respectively as mean±SEM. Statistical analyses wereperformed using GraphPad Prism software and significant difference wasassessed by t test (*<0.05 and **<0.01). The levels were normalized toβ-actin expression and percentage was calculated as the percent relativeto protein synthesis levels from mobile limb of control mice(vehicle-treated) which correspond to 100%. In all three immobilizedmuscles from vehicle-treated mice there is a significant reduction ofprotein synthesis. Interestingly, there is a complete recovery ofprotein synthesis in tibialis anterior and quadriceps and a partialrecovery of protein synthesis in gastrocnemius from compound-3-treatedimmobilized hindlimbs, suggesting that compound 3 could inhibits theISR-induced repression of protein synthesis.

For immunohistochemical analysis of cross-sectional area (CSA),gastrocnemius from mobile and immobile hind limbs were submergedindividually in optimal cutting temperature (OCT) compound (Tissue-Tek;Sakura) at resting length, and frozen in isopentane cooled with liquidnitrogen. Cross-sections (10-μm thick) from the mid-belly of the musclewas obtained with a cryostat (Leica) and immunostained with ATF4antibody (Abcarn). A HRP-polymer conjugated secondary antibody (BiocareMedical, MM620L) followed by diaminobenzidine substrate incubation(ImmPACT DAB—Vector, SK-4105) were employed to detect puromycinylatedstructures in CSA.

Muscle fiber CSAs were visualized with a Zeiss Axio Lab.A1 microscopeand an Axiocam (Zeiss) digital camera. ATF4 staining in CSA is shown inFIG. 10D. Histological muscle sections from immobilized hind limb showfibers stained with ATF4, indicating the activation of the ISR. Asexpected, there is a strong correlation between the activation of theISR pathway and the reduction of protein synthesis in immobilizedmuscles.

Example B9—Cachexia-Induced Muscle Atrophy

Wild type six-weeks-old male Ba1b/c mice obtained from the vivariumFundación Ciencia & Vida Chile (Santiago, Chile) were used. Mice werehoused in independent plastic cages in a room maintained at 25° C. witha 12-h:12-h light:dark cycle.

1×10⁶ CT26 colon carcinoma cell line (ATCC #CRL-2638, ATCC Manassas,Va.) were injected subcutaneously in the right lower flank of eachanimal for induction of cachexia-induced muscle atrophy as described(Nat Commun. 2012 Jun. 12; 3:896). Non-injected animals were used ascontrols. At day 6 post tumor-cell injection, animals were randomizedinto two groups and treated with 10 mg/kg of compound 3 formulated in50% Polyethylene glycol (PEG-400) in distilled water, or with vehicle(50% PEG-400 in distilled water) by daily oral gavage for 13 days.

For in vivo measurements of protein synthesis, 30 min before the studyends, animals were injected intraperitoneally with puromycin(Sigma-Aldrich, P8833) at 0.04 μmol/g body weight in a volume of 200 μLof PBS. After 13 days of daily dosage, the animals were sacrificed andgastrocnemius, quadriceps and tibialis anterior muscles were dissectedand weighed from both hindlimbs to assess muscle atrophy.

Upon collection, muscles were immediately frozen in liquid nitrogen andthen stored at −80° C. The frozen muscles were then homogenized with a T10 basic ULTRA-TURRAX (IKa) in ice-cold buffer lysis (Cell Signaling9803) and protease and phosphatase inhibitors (Roche). Lysates weresonicated for 3 min and centrifuged at 13,000 rpm for 20 minutes at 4°C. Protein concentration in supernatants was determined using BCAProtein Assay Kit (Pierce). Equal amount of proteins was loaded onSDS-PAGE gels. Proteins were transferred onto 0.2 um PVDF membranes(BioRad) and probed with primary antibodies diluted in Tris-bufferedsaline supplemented with 0.1% Tween 20 and 3% bovine serum albumin.

Puromycin (12D10) (Merck Millipore) and β-actin (Sigma-Aldrich)antibodies were used as primary antibodies. A HRP-conjugated secondaryantibody (Rockland) was employed to detect immune-reactive bands usingenhanced chemiluminescence (ECL Western Blotting Substrate, Pierce).Quantification of protein bands was done by densitometry using ImageJsoftware.

Gastrocnemius, quadriceps, and tibialis anterior muscle weight fromanimals injected with CT26 tumor cells and treated with either vehicleor compound 3 are shown in FIGS. 11A, 11B, and 11C respectively.Treatment with compound 3 prevented the CT26-induced muscle weight loss.

Percent of protein synthesis in gastrocnemius, quadriceps and tibialisanterior from animals injected with CT26 tumor cells and treated witheither vehicle or compound 3 are shown in FIGS. 11D, 11E and 11Frespectively. The levels were normalized to β-actin expression andpercentage was calculated as the percent relative to protein synthesislevels from muscle section of control mice which correspond to 100%.Data is shown as individual values and mean±standard error of mean(SEM). Statistical analyses were performed using GraphPad Prism softwareand significant difference was assessed by t test (*<0.05). Treatmentswith compound 3 in tumor-induced muscle-wasting animals significantlyincrease protein synthesis in quadriceps and tibialis anterior comparedto vehicle-treated tumor-injected animals.

Example B10—Tumor growth and density model

Wild type six-weeks-old male Ba1b/c mice obtained from the vivariumFundación Ciencia & Vida Chile (Santiago, Chile) were used. Mice werehoused in independent plastic cages in a room maintained at 25° C. witha 12-h:12-h light:dark cycle.

1×10⁶ CT26 colon carcinoma cell line (ATCC #CRL-2638, ATCC Manassas,Va.) were injected subcutaneously in the right lower flank of eachanimal as described (Nat Commun. 2012 Jun. 12; 3:896). Non-injectedanimals were used as controls. At day 6 post tumor-cell injection, meantumor volume was about 100 mm³, animals were weighed and randomized intotwo groups and treated with 10 mg/kg of compound 3 formulated in 50%Polyethylene glycol (PEG-400) in distilled water, or with vehicle (50%PEG-400 in distilled water) by daily oral gavage for 13 days.

At the end of the study, tumors were measured with digital caliper andtumors volumes, expressed in mm³, were calculated with the followingformula:

Tumor volume(mm ³)=(a×b ²)/2

where “a” is the largest perpendicular diameter and “b” is the smallestdiameter. Animals were then sacrificed and tumors were extracted andweighed. The volumes and weight of the tumors of each animal are shownin FIGS. 12A and 12B respectively. Tumor density was calculated asweight/volume ratio for each animal and is shown in FIG. 12C. Barsrepresent mean±SEM. Statistical analyses were performed using GraphPadPrism software and significant difference was assessed by t test(*<0.05).

As shown in FIGS. 12A-12C, compound 3 does not reduce tumor volume butsignificantly reduce the tumor density, suggesting that treatment withISR-inhibitor compounds could make tumors less compact and hence moreaccessible to some tumor-directed therapies such as checkpointsinhibitors, adoptive cell transfer, monoclonal antibodies or cytokinesthat boost immune system.

Example B11—Protein Synthesis with a Cell-Free System

The expression of the green fluorescence protein (GFP) was evaluatedusing the 1-Step Human In vitro Protein Expression Kit based on HeLacell lysates (ThermoFisher Scientific). HeLa lysate, accessory proteins,reaction mix and pCFE-GFP plasmid from the kit were thawed in ice.Reactions were prepared at room temperature in a 96-well optical plateby adding 12.5 μL of HeLa lysate, 2.5 μL accessory proteins, 5 μLreaction mix, 1 μg of pCFE-GFP plasmid and 1 μM of test compounds in 5μL or 5 μL of distilled H₂O as a basal expression of GFP (vehicle). Awell with dH₂O instead of pCFE-GFP plasmid was used as basalautofluorescence of the reaction. All reactions were made in duplicated.Fluorescence intensity was measured by a multi-mode microplate reader(Synergy-4; Biotek) during 6-hour treatments and capturing fluorescenceat 15-minute intervals with 485/20 and 528/20 excitation and emissionfilters.

Relative fluorescence intensity (RFU) of GFP resulting from cell-freeexpression treated with compounds 152 or 153 or vehicle are shown inFIG. 13A. Comparison of RFU of GFP at 6 hours is shown in FIG. 13B. Theaddition of compounds 152 or 153 to the kit's reaction mix increase theexpression of GFP and hence its fluorescence up to 4-fold compared tothe expression obtained using the kit's reagents alone.

Example B12—Protein Synthesis with a Yeast Cell-Based Assay

Two GS115H Pichia pastoris yeast strains that stably expressphospholipase C protein (PLC) under the control of a methanol-induciblepromoter (pAOX-PLC) or a constitutive promoter (pGAP-PLC) were used toassess the secretion levels of PLC and its enzymatic activity. pAOX-PLCand pGAP-PLC yeast single colonies were inoculated in 2 ml of YPD (1%yeast extract, 2% peptone, 2% glucose) and grown at 30° C. in a deep24-well microplate in a shaking incubator for 16-18 h at 250 rpm. Thesecultures were diluted to an OD600 of 1 in 2 m1 of YPM (1% yeast extract,2% peptone, 100 mM phosphate buffer pH 6 and 0.5% methanol) or 2 ml ofYPM containing 10 μM of compound 152 to induce gene expression andincubated at 30° C. in a shaking incubator at 250 rpm. Methanol wasadded every 24 h in order to maintain 0.5% methanol concentration.Condition without compound 152 was used as a control for basal secretionand subsequent activity assessment of PLC. After 72 h of induction,cells were harvested by centrifugation and the supernatant analyzed forprotein expression by SDS-PAGE and PLC activity.

Gels were stained with 0.1% Coomassie Blue R250 in 10% acetic acid, 50%methanol, and 40% H₂O for 20 minutes. Stained gel was then washed twicefor 2 hours with 10% acetic acid, 50% methanol and 40% dH₂O until theCoomassie Blue background was nearly clear. Photographs of the gels weretaken in a gel imaging system. The secretion of PLC for pAOX-PLC orpGAP-PLC strains in the presence or absence of compound 152 are shown bythe arrows in FIGS. 14A and 14B. Secretion of PLC under the compound152-treatment is shown in duplicates.

PLC activity was measured in 96 well microplates using 1 mMO—(4-Nitrophenylphosphoryl)choline as a substrate. The assay was carriedout at 50° C. in a 96 microwell plate by incubating 10 μL of culturesupernatant, 10 μL 100 mM NPPC and 80 μL of 250 mM HEPES pH 7, 60%sorbitol, 0.1 mM ZnCl₂. Absorbance at 405 nm was monitored every 30 sfor 1 h at 50° C. in a Synergy HT microplate reader (Biotek). 1 PLC unitis defined as the amount of enzyme releasing 1 nmol of p-nitrophenol perminute. Activity of PLC secreted from pAOX-PLC or pGAP-PLC strains inthe presence or absence of compound 152 is shown in FIGS. 14C and 14Drespectively as mean±SEM. Fold change was calculated as the activityrelative to the activity levels from untreated yeasts. Statisticalanalyses were performed using GraphPad Prism software and significantdifference was assessed by t test (*<0.05).

Results show that treatment with an ISR-inhibitor compound increases thesynthesis of a heterologous protein and also its secretion in acell-based system. In addition, the activity of the over expressedprotein also increases during these conditions as shown in FIGS. 14C and14D.

Example B13—Protein Synthesis with a CHO Cell-Based Assay

CHO cells were maintained at 37° C. and 5% CO₂ in DMEM supplemented with10% fetal bovine serum (FBS), 2 mM L-glutamine, 100 U/ml penicillin, and100 μg/ml streptomycin. After reaching 80% of confluence, cells weredetached and seeded on 6-well plates in complete media, allowed torecover for 48 h. Cells were then washed three times with PBS andtreated with compound 152 and 153 at 1 μM, 5 μM or 10 μM 1 mL of mediawithout FBS for 24 h. Treatment with 0.1% DMSO was used as control(vehicle). After 24 h treatment, supernatant (SN) which containssecreted proteins was extracted and protease and phosphatase inhibitors(Roche) were added to each sample. SN were centrifuged at 2,000 g for 10min to discard any cellular debris and 900 μL SN were transferred toempty microtubes with 400 μL methanol by mixing well. 200 μL ofchloroform was added to the mix and then samples were centrifuged at14,000 g for 2 minutes. Top aqueous layer was discarded by pipetting offand 400 μL methanol was added to each sample by mixing well. Sampleswere then centrifuged at 17,000 g for 8 minutes and methanol wasdiscarded by pipetting off without disturbing the protein pellet.Samples were left dry at room temperature and pellets were resuspendedwith SDS-PAGE sample buffer. Secreted proteins were analyzed by SDS-PAGEand Coomassie staining. Gels were stained with 0.1% Coomassie Blue R250in 10% acetic acid, 50% methanol, and 40% H₂O for 20 minutes. Stainedgel was then washed twice for 2 hours with 10% acetic acid, 50% methanoland 40% dH₂O until the Coomassie Blue background was nearly clear.Photographs of the gels were taken in a gel imaging system.

Total protein secretion from CHO cells treated with compound 152 or 153at the indicated concentration or vehicle alone for 24 hours are shownin FIG. 15A. Quantification of protein bands from the gel was done bydensitometry using ImageJ. Percent of secreted proteins in eachtreatment is shown in FIG. 15B. Percentage was calculated as the percentrelative to protein secretion levels from vehicle-treated CHO cellswhich correspond to 100%. Treatment with ISR-inhibitor compounds canincrease the secretion of proteins in a cell-based assay and could beused as enhancers of recombinant proteins in those systems.

All references throughout, such as publications, patents, patentapplications and published patent applications, are incorporated hereinby reference in their entireties.

1-9. (canceled)
 10. A compound of formula (XX-I-2):

or a pharmaceutically acceptable salt thereof; wherein: R^(Y5) ishydrogen or C₁-C₆ alkyl; R^(N) is hydrogen or C₁-C₆ alkyl; A¹³ isselected from the group consisting of: C₆-C₁₀ aryl optionallysubstituted with one or more R⁹⁵ substituents; and 5-10 memberedheteroaryl optionally substituted with one or more R⁹⁵ substituents; R⁹⁵is selected, independently at each occurrence, from the group consistingof halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆haloalkyl), —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂,—NR^(95-a)R^(95-b), —CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆ haloalkyl),—C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆ haloalkyl), —C(O)NR^(95-a)R^(95-b),—S(O)₂OH, —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂,—S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,—S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(95-a)R^(95-b), —OC(O)H,—OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H,—N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆alkyl)C(O)H, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),—OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ alkyl), and—N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ haloalkyl); wherein R^(95-a) and R^(95-b)are taken together with the nitrogen atom which bears them to form a3-10 membered heterocycle; R⁸⁸ is selected from the group consisting ofhydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —C(O)(C₁-C₆ alkyl), —C(O)(C₁-C₆haloalkyl), —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl),—C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆alkyl)₂, —C(O)N(C₁-C₆ haloalkyl)₂, —C(O)NR^(88-a)R^(88-b), —S(O)₂OH,—S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂,—S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,—S(O)₂N(C₁-C₆ haloalkyl), and —S(O)₂NR^(88-a)R^(88-b); wherein R^(88-a)and R^(88-b) are taken together with the nitrogen atom which bears themto form a 3-10 membered heterocycle; R⁸⁹ is selected, independently ateach occurrence, from the group consisting of hydrogen, halogen, C₁-C₆alkyl, C₁-C₆ haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH,—S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —NH(C₁-C₆haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(89-a)R^(89-b),—CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂,—C(O)N(C₁-C₆ haloalkyl)₂, —C(O)NR^(89-a)R^(89-b), —S(O)₂OH,—S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂,—S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,—S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(89-a)R^(89-b), —OC(O)H,—OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H,—N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆alkyl)C(O)H, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),—OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ alkyl), and—N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ haloalkyl), wherein R^(89-a) and R^(89-b)are taken together with the nitrogen atom which bears them to form a3-10 membered heterocycle. 11-15. (canceled)
 16. The compound of claim10, or a pharmaceutically acceptable salt thereof, wherein the compoundis selected from the group consisting of

or a pharmaceutically acceptable salt thereof.
 17. A pharmaceuticalcomposition comprising a compound of claim 10, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 18.A method of treating a disease or disorder mediated by an integratedstress response (ISR) pathway in an individual in need thereofcomprising administering to the individual a therapeutically effectiveamount of a compound of claim 10, or a pharmaceutically acceptable saltthereof.
 19. A method of producing a protein, comprising contacting aeukaryotic cell comprising a nucleic acid encoding the protein with thecompound of claim 10, or a salt thereof.
 20. A method of culturing aeukaryotic cell comprising a nucleic acid encoding a protein, comprisingcontacting the eukaryotic cell with an in vitro culture mediumcomprising the compound of claim 10, or a salt thereof.
 21. A method ofproducing a protein, comprising contacting a cell-free protein synthesis(CFPS) system comprising eukaryotic initiation factor 2 (eIF2) and anucleic acid encoding a protein with the compound of claim 10, or a saltthereof.
 22. An in vitro cell culture medium, comprising the compound ofclaim 10, or a salt thereof and nutrients for cellular growth.
 23. Acell-free protein synthesis (CFPS) system comprising eukaryoticinitiation factor 2 (eIF2) and a nucleic acid encoding a protein withthe compound of claim 10, or a salt thereof.
 24. The method of claim 18,wherein the disease or disorder mediated by an integrated stressresponse (ISR) pathway is a neurodegenerative disease, an inflammatorydisease, an autoimmune disease, a metabolic syndrome, a cancer, avascular disease, a musculoskeletal disease, an ocular disease, or agenetic disorder.
 25. The method of claim 24, wherein the disease ordisorder mediated by an integrated stress response (ISR) pathway is aneurodegenerative disease.
 26. The method of claim 25, wherein theneurodegenerative disease is vanishing white matter disease.
 27. Themethod of claim 25, wherein the neurodegenerative disease is amyotrophiclateral sclerosis (ALS).
 28. The method of claim 25, wherein theneurodegenerative disease is frontotemporal dementia (FTD).
 29. Themethod of claim 24, wherein the disease or disorder mediated by anintegrated stress response (ISR) pathway is an inflammatory disease. 30.The method of claim 24, wherein the disease or disorder mediated by anintegrated stress response (ISR) pathway is an autoimmune disease. 31.The method of claim 24, wherein the disease or disorder mediated by anintegrated stress response (ISR) pathway is a metabolic syndrome. 32.The method of claim 24, wherein the disease or disorder mediated by anintegrated stress response (ISR) pathway is a cancer.
 33. The method ofclaim 32, wherein the cancer is prostate cancer.
 34. The method of claim24, wherein the disease or disorder mediated by an integrated stressresponse (ISR) pathway is a musculoskeletal disease.
 35. The method ofclaim 34, wherein the musculoskeletal disease is muscular atrophy. 36.The method of claim 24, wherein the disease or disorder mediated by anintegrated stress response (ISR) pathway is a genetic disorder.
 37. Themethod of claim 36, wherein the genetic disorder is Down syndrome. 38.The method of claim 24, wherein the disease or disorder mediated by anintegrated stress response (ISR) pathway is a vascular disease.
 39. Themethod of claim 24, wherein the disease or disorder mediated by anintegrated stress response (ISR) pathway is an ocular disease.
 40. Thecompound of claim 10, or a pharmaceutically acceptable salt thereof,wherein R^(Y5) is hydrogen.
 41. The compound of claim 10, or apharmaceutically acceptable salt thereof, wherein R^(N) is hydrogen. 42.The compound of claim 10, or a pharmaceutically acceptable salt thereof,wherein A¹³ is C₆-C₁₀ aryl optionally substituted with one or more R⁹⁵substituents.
 43. The compound of claim 10, or a pharmaceuticallyacceptable salt thereof, wherein A¹³ is selected from the groupconsisting of

wherein the * represents the attachment point to the remainder of themolecule.
 44. The compound of claim 10, or a pharmaceutically acceptablesalt thereof, wherein A¹³ is selected from the group consisting of

wherein the * represents the attachment point to the remainder of themolecule.
 45. The compound of claim 10, or a pharmaceutically acceptablesalt thereof, wherein A¹³ is

wherein the * represents the attachment point to the remainder of themolecule.
 46. The compound of claim 10, or a pharmaceutically acceptablesalt thereof, wherein A¹³ is

wherein the * represents the attachment point to the remainder of themolecule.
 47. The compound of claim 10, or a pharmaceutically acceptablesalt thereof, wherein R⁸⁸ is hydrogen.
 48. The compound of claim 10, ora pharmaceutically acceptable salt thereof, wherein R⁸⁹ is selected,independently at each occurrence, from the group consisting of hydrogenand halogen.
 49. The compound of claim 10, or a pharmaceuticallyacceptable salt thereof, wherein the moiety

wherein # represents the attachment point to the remainder of themolecule, is

wherein # represents the attachment point to the remainder of themolecule.
 50. A compound of formula (1-3):

or a pharmaceutically acceptable salt thereof; wherein: X² is CH or N;R^(Y1) is hydrogen or C₁-C₆ alkyl; Y² is selected from the groupconsisting of a bond, NR^(Y2), and O; provided that when X² is N, thenY² is a bond; R^(Y2) is hydrogen or C₁-C₆ alkyl; r and s, independentlyof each other, are 0, 1, or 2; A¹ is selected from the group consistingof: a substituent of formula (A¹-a)

wherein * represents the attachment point to the remainder of themolecule; Z¹ is selected from the group consisting of CR^(Z1-1)R^(Z1-2),NR^(Z1-2) O, S, and —CR^(Z1-1)═CR^(Z1-1)—;  wherein R^(Z1-1) is H or R″;and R^(Z1-2) is H or R¹⁴; Z² is selected from the group consisting ofCR^(Z2-1)R^(Z2-2), NR^(Z2-2); O, S, and —CR^(Z2-1)═CR^(Z2-1)—;  whereinR^(Z2-1) is H or R¹⁴; and R^(Z2-2) is H or R¹⁴; Z³, independently ateach occurrence, is C or N, provided that at least one Z³ is C; R¹³ ishydrogen or R¹⁴, or R¹³ and R^(Z1-2) are taken together to form a doublebond between the carbon atom bearing R¹³ and Z¹, or R¹³ and R^(Z2-2) aretaken together to form a double bond between the carbon atom bearing R¹³and Z²; and x1 is 1, 2, 3, or 4, and at least one R¹⁴ is halogen; R¹⁴ isselected, independently at each occurrence, from the group consisting ofhalogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆haloalkyl), —SH, —S(C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆alkyl), —NH(C₁-C₆ haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂,—NR^(14-a)R^(14-b), —CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆ haloalkyl),—C(O)N(C₁-C₆ alkyl)₂, —C(O)N(C₁-C₆ haloalkyl)₂, —C(O)NR^(14-a)R^(14-b),—S(O)₂OH, —S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂,—S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,—S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(14-a)R^(14-b), —OC(O)H,—OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H,—N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆alkyl)C(O)H, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),—OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ alkyl), and—N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ haloalkyl); wherein R^(14-a) and R^(14-b)are taken together with the nitrogen atom which bears them to form a3-10 membered heterocycle; A² is C₆-C₁₀ aryl substituted by at least onehalogen substituent and optionally further substituted with one or moreR¹⁶ substituents, or 5-10 membered heteroaryl substituted by at leastone halogen substituent and optionally further substituted with one ormore R¹⁶ substituents; R¹⁶ is selected, independently at eachoccurrence, from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆alkyl), —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —NH(C₁-C₆haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(16-a)R^(16-b),—CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂,—C(O)N(C₁-C₆ haloalkyl)₂, —C(O)NR^(16-a)R^(16-b), —S(O)₂OH,—S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂,—S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,—S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(16-a)R^(16-b), —OC(O)H,—OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H,—N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆alkyl)C(O)H, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),—OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ alkyl), and—N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ haloalkyl); wherein R^(16-a) and R^(16-b)are taken together with the nitrogen atom which bears them to form a3-10 membered heterocycle; R^(1a) and R^(1b) are independently selectedfrom the group consisting of hydrogen, C₁-C₆ alkyl, and halogen; R^(2a)and R^(2b) are independently selected from the group consisting ofhydrogen, C₁-C₆ alkyl, and halogen; when present, R^(3a) and R^(3b) areindependently at each occurrence selected from the group consisting ofhydrogen, C₁-C₆ alkyl, and halogen; when present, R^(4a) and R^(4b) areindependently at each occurrence selected from the group consisting ofhydrogen, C₁-C₆ alkyl, and halogen; or alternatively, R^(1a) and R^(2a)are taken together to form a C₁-C₆ alkylene moiety; or alternatively,R^(1a) and an R^(3a) moiety, when present, are taken together to form aC₁-C₆ alkylene moiety, and R^(1b) and the R^(3b) in the geminal positionto the R^(3a) taken together with R^(1a), are both hydrogen; oralternatively, an R^(3a) moiety, when present, and an R^(4a) moiety,when present, are taken together to form a C₁-C₆ alkylene moiety, andthe R^(3b) in the geminal position to the R^(3a) taken together with theR^(4a) moiety and the R^(4b) in the geminal position to the R^(4a) takentogether with the R^(3a) moiety, are both hydrogen; R^(9a) and R^(9b)are taken together to form an oxo (═O) substituent or an imido (═NH)substituent, or alternatively, R^(9a) and R^(9b) are both hydrogen;R^(10a) is selected from the group consisting of hydrogen, —OR^(10a-a),and —NR^(10a-b)R^(10a-c); R^(10b) is hydrogen; R^(12a) and R^(12b) aretaken together to form an oxo (═O) substituent, or alternatively,R^(12a) and R^(12b) are both hydrogen; R^(10a-a) is selected from thegroup consisting of hydrogen, C₁-C₆ alkyl, and C₁-C₆ haloalkyl; orR^(10a-a) and R^(Y2) may be taken together to form a carbonyl (C═O)moiety; and R^(10a-b) and R^(10a-c), independently of each other, areselected from the group consisting of hydrogen, C₁-C₆ alkyl, and C₁-C₆haloalkyl.
 51. A compound of formula (2-3):

or a pharmaceutically acceptable salt thereof; wherein: X¹ and X²,independently of each other, are CH or N; provided that at least one ofX¹ and X² is CH; Y¹ is selected from the group consisting of a bond,NR^(Y1), and O; provided that when X¹ is N, then Y¹ is a bond; R^(Y1) ishydrogen or C₁-C₆ alkyl; Y² is selected from the group consisting of abond, NR^(Y2), and O; provided that when X² is N, then Y² is a bond;R^(Y2) is hydrogen or C₁-C₆ alkyl; q1 is 1; r and s, independently ofeach other, are 0, 1, or 2; A¹ is C₆-C₁₀ aryl substituted by at leastone halogen substituent and optionally further substituted with one ormore R¹⁴ substituents, or 5-10 membered heteroaryl substituted by atleast one halogen substituent and optionally further substituted withone or more R¹⁴ substituents; R¹⁴ is selected, independently at eachoccurrence, from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆alkyl), —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —NH(C₁-C₆haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(14-a)R^(14-b),—CN, —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂,—C(O)N(C₁-C₆ haloalkyl)₂, —C(O)NR^(14-a)R^(14-b), —S(O)₂OH,—S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂,—S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,—S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(14-a)R^(14-b), —OC(O)H,—OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H,—N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆alkyl)C(O)H, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),—OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ alkyl), and—N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ haloalkyl); wherein R^(14-a) and R^(14-b)are taken together with the nitrogen atom which bears them to form a3-10 membered heterocycle; A² is C₆-C₁₀ aryl substituted by at least onehalogen substituent and optionally further substituted with one or moreR¹⁶ substituents, or 5-10 membered heteroaryl substituted by at leastone halogen substituent and optionally further substituted with one ormore R¹⁶ substituents; R¹⁶ is selected, independently at eachoccurrence, from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆haloalkyl, —OH, —O(C₁-C₆ alkyl), —O(C₁-C₆ haloalkyl), —SH, —S(C₁-C₆alkyl), —S(C₁-C₆ haloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —NH(C₁-C₆haloalkyl), —N(C₁-C₆ alkyl)₂, —N(C₁-C₆ haloalkyl)₂, —NR^(16-b), —CN,—C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)O(C₁-C₆ haloalkyl), —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)NH(C₁-C₆ haloalkyl), —C(O)N(C₁-C₆ alkyl)₂,—C(O)N(C₁-C₆ haloalkyl)₂, —C(O)NR^(16-a)R^(16-b), —S(O)₂OH,—S(O)₂O(C₁-C₆ alkyl), —S(O)₂O(C₁-C₆ haloalkyl), —S(O)₂NH₂,—S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ haloalkyl), —S(O)₂N(C₁-C₆ alkyl)₂,—S(O)₂N(C₁-C₆ haloalkyl)₂, —S(O)₂NR^(16-a)R^(16-b), —OC(O)H,—OC(O)(C₁-C₆ alkyl), —OC(O)(C₁-C₆ haloalkyl), —N(H)C(O)H,—N(H)C(O)(C₁-C₆ alkyl), —N(H)C(O)(C₁-C₆ haloalkyl), —N(C₁-C₆alkyl)C(O)H, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)(C₁-C₆haloalkyl), —N(C₁-C₆ haloalkyl)C(O)H, —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆alkyl), —N(C₁-C₆ haloalkyl)C(O)(C₁-C₆ haloalkyl), —OS(O)₂(C₁-C₆ alkyl),—OS(O)₂(C₁-C₆ haloalkyl), —N(H)S(O)₂(C₁-C₆ alkyl), —N(H)S(O)₂(C₁-C₆haloalkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂(C₁-C₆ haloalkyl), —N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ alkyl), and—N(C₁-C₆ haloalkyl)S(O)₂(C₁-C₆ haloalkyl); wherein R^(16-a) and R^(16-b)are taken together with the nitrogen atom which bears them to form a3-10 membered heterocycle; R^(1a) and R^(1b) are independently selectedfrom the group consisting of hydrogen, C₁-C₆ alkyl, and halogen; R^(2a)and R^(2b) are independently selected from the group consisting ofhydrogen, C₁-C₆ alkyl, and halogen; when present, R^(3a) and R^(3b) areindependently at each occurrence selected from the group consisting ofhydrogen, C₁-C₆ alkyl, and halogen; when present, R^(4a) and R^(4b) areindependently at each occurrence selected from the group consisting ofhydrogen, C₁-C₆ alkyl, and halogen; or alternatively, R^(1a) and R^(2a)are taken together to form a C₁-C₆ alkylene moiety; or alternatively,R^(1a) and an R^(3a) moiety, when present, are taken together to form aC₁-C₆ alkylene moiety, and R^(1b) and the R^(3b) in the geminal positionto the R^(3a) taken together with R^(1a), are both hydrogen; oralternatively, an R^(3a) moiety, when present, and an R^(4a) moiety,when present, are taken together to form a C₁-C₆ alkylene moiety, andthe R^(3b) in the geminal position to the R^(3a) taken together with theR^(4a) moiety and the R^(4b) in the geminal position to the R^(4a) takentogether with the R^(3a) moiety, are both hydrogen; R^(5a) and R^(5b)are taken together to form an oxo (═O) substituent or an imido (═NH)substituent, or alternatively; R^(6a) is hydrogen; R^(6b) is hydrogen;R^(9a) and R^(9b) are taken together to form an oxo (═O) substituent oran imido (═NH) substituent, or alternatively, R^(9a) and R^(9b) are bothhydrogen; R^(10a) is selected from the group consisting of hydrogen,—OR^(10a-a), and —NR^(10a-b)R^(10a-c); R^(10b) is hydrogen; R^(12a) andR^(12b) are taken together to form an oxo (═O) substituent, oralternatively, R^(12a) and R^(12b) are both hydrogen; R^(10a-a) isselected from the group consisting of hydrogen, C₁-C₆ alkyl, and C₁-C₆haloalkyl; or R^(10a-a) and R^(Y2) may be taken together to form acarbonyl (C═O) moiety; R^(10a-b) and R^(10a-c), independently of eachother, are selected from the group consisting of hydrogen, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and provided that when X² is N, then: A¹ is C₆-C₁₀aryl substituted by at least two halogen substituents and optionallyfurther substituted with one or more 10⁴ substituents, or 5-10 memberedheteroaryl substituted by at least two halogen substituents andoptionally further substituted with one or more R¹⁴ substituents; and A²is C₆-C₁₀ aryl substituted by at least two halogen substituents andoptionally further substituted with one or more 10⁶ substituents, or5-10 membered heteroaryl substituted by at least two halogensubstituents and optionally further substituted with one or more R¹⁶substituents.